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Ujihira Y, Tan SPF, Scotcher D, Galetin A. Genotype, Ethnicity, and Drug-Drug Interaction Modeling as Means of Verifying Transporter Biomarker PBPK Model: The Coproporphyrin-I Story. CPT Pharmacometrics Syst Pharmacol 2025; 14:941-953. [PMID: 40065524 PMCID: PMC12072222 DOI: 10.1002/psp4.70008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/22/2025] [Accepted: 02/10/2025] [Indexed: 05/14/2025] Open
Abstract
Coproporphyrin-I (CP-I) is a selective endogenous biomarker of organic anion-transporting polypeptide (OATP)1B. Multiple CP-I PBPK models with differing input parameters have been reported so far. This study proposed a harmonized CP-I PBPK model and evaluated its ability to predict the effect of ethnicity, SLCO1B1 genotype c.521T>C, and sex on CP-I baseline and CP-I-drug interactions using the largest clinical dataset to date. The CP-I PBPK model successfully predicted CP-I plasma baseline from 731 subjects, with 97% of predictions within 1.5-fold of the observed data. Prediction of weak, moderate, and strong OATP1B-mediated interactions with probenecid, low-dose cyclosporine, and rifampicin, respectively, was evaluated with 21 datasets. Overall, > 76% of CP-I CmaxR and AUCR were predicted within the Guest criterion. In vivo OATP1B Ki estimated by the biomarker model was up to ninefold lower compared to in vitro values. Sensitivity analyses showed differences in estimated in vivo Ki depending on the assumed contribution of non-inhibited/parallel pathway (renal) for CP-I (0%-15%), highlighting the need to consider this factor when using biomarker PBPK models for such purposes. Finally, the appropriate metric for monitoring CP-I was evaluated for inhibitors with different potency and PK relative to CP-I. In the case of strong/moderate OATP1B inhibitors with short t1/2, CmaxR was the most sensitive metric for monitoring CP-I OATP1B interactions, whereas both CmaxR and AUCR were applicable for inhibitors with long t1/2. The current study provides a harmonized CP-I PBPK model, together with recommendations to support the optimal design of prospective clinical trials for the assessment of OATP1B-mediated DDIs using this biomarker.
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Affiliation(s)
- Yuki Ujihira
- Centre for Applied Pharmacokinetic Research, School of Health SciencesUniversity of ManchesterManchesterUK
- Laboratory for Safety Assessment and ADME, Pharmaceuticals Research CenterAsahi Kasei Pharma CorporationShizuokaJapan
| | - Shawn Pei Feng Tan
- Centre for Applied Pharmacokinetic Research, School of Health SciencesUniversity of ManchesterManchesterUK
| | - Daniel Scotcher
- Centre for Applied Pharmacokinetic Research, School of Health SciencesUniversity of ManchesterManchesterUK
| | - Aleksandra Galetin
- Centre for Applied Pharmacokinetic Research, School of Health SciencesUniversity of ManchesterManchesterUK
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2
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Bonkovsky HL, Ma CD, Araque M, Tiley JB, Brouwer KLR, Stölzel U. Understanding Coproporphyrins and Their Disposition: Coproporphyrinuria is Common, of Diverse Cause, and Rarely Indicates Porphyria. Am J Med 2025:S0002-9343(25)00225-6. [PMID: 40228600 DOI: 10.1016/j.amjmed.2025.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Revised: 03/30/2025] [Accepted: 04/01/2025] [Indexed: 04/16/2025]
Abstract
Coproporphyrins (CPs) are often mildly increased in plasma and urine, which leads to erroneous overdiagnosis of porphyrias. Herein we provide an overview of normal CP metabolism and factors that influence its disposition. We reviewed extant literature and here summarize and put into context current knowledge of CP metabolism and its disposition. CPs are formed as byproducts of normal heme synthesis. Normally they are removed chiefly by hepatocytes into bile and then stool. Organic anion-transporting peptides (OATPs) and multidrug resistance-associated proteins facilitate the uptake of CPs into epithelial cells and removal. Xenobiotics inhibit the activities of multidrug resistance-associated proteins and/or OATPs and affect the metabolism and disposition of CPs. CP concentrations are used as endogenous probes for assessing altered functions of OATPs. Diverse liver diseases and disorders lead to decreased secretion of CPs into bile and thus to increased concentrations of CPs in plasma and urine. Usually, mild to moderate increases in urinary CPs are due to alcohol, heavy metals, drug effects on transporters, or nonporphyric liver diseases not to porphyrias or to other inherited syndromes.
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Affiliation(s)
- Herbert L Bonkovsky
- Section on Gastroenterology & Hepatology, Wake Forest University School of Medicine and Atrium Health Wake Forest Baptist Medicine, Winston-Salem, NC.
| | - Christopher D Ma
- Department of Medicine, University of Miami School of Medicine, Miami, FL
| | - Manuela Araque
- Department of Medicine, University of Miami School of Medicine, Miami, FL
| | - Jacqueline B Tiley
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill
| | - Ulrich Stölzel
- Department of Internal Medicine II and Porphyria Center, Klinikum Chemnitz, Chemnitz, Germany
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3
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Fashe MM, Tiley JB, Lee CR. Mechanisms of altered hepatic drug disposition during pregnancy: small molecules. Expert Opin Drug Metab Toxicol 2025; 21:445-462. [PMID: 39992297 PMCID: PMC11961323 DOI: 10.1080/17425255.2025.2470792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/01/2025] [Accepted: 02/19/2025] [Indexed: 02/25/2025]
Abstract
INTRODUCTION Pregnancy alters the systemic exposure and clearance of many hepatically cleared drugs that are commonly used by obstetric patients. Understanding the molecular mechanisms underlying the changes in factors that affect hepatic drug clearance (blood flow, protein binding, and intrinsic clearance) is essential to more precisely predict systemic drug exposure and dose requirements in obstetric patients. AREAS COVERED This review (1) summarizes the anatomic, physiologic, and biochemical changes in maternal hepatic, cardiovascular, endocrine, and renal systems relevant to hepatic drug clearance and (2) reviews the molecular mechanisms underlying the altered hepatic metabolism and intrinsic clearance of drugs during pregnancy via a comprehensive PubMed search. It also identifies knowledge gaps in the molecular mechanisms and factors that modulate hepatic drug clearance during pregnancy. EXPERT OPINION Pharmacokinetic studies have shown that pregnancy alters systemic exposure, protein binding, and clearance of many drugs during gestation in part due to pregnancy-associated decreases in plasma albumin, increases in organ blood flow, and changes in the activity of drug-metabolizing enzymes (DMEs) and transporters. The changes in the activity of certain DMEs and transporters during pregnancy are likely driven by hormonal-changes that inhibit their activity or alter the expression of these proteins through activation of transcription factors.
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Affiliation(s)
- Muluneh M. Fashe
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
| | - Jacqueline B. Tiley
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
| | - Craig R. Lee
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
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4
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Ishikawa R, Misawa T, Demizu Y, Saito Y, Kikura-Hanajiri R, Saito K. Comprehensive invitro evaluation of the inhibitory effects of relatively high molecular weight peptides on drug-drug interaction-associated four liver transporters and its association with physicochemical properties. Drug Metab Pharmacokinet 2025; 61:101055. [PMID: 40043642 DOI: 10.1016/j.dmpk.2025.101055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 01/28/2025] [Accepted: 01/30/2025] [Indexed: 03/25/2025]
Abstract
In recent years, advances in peptide synthesis have enabled the construction of relatively high molecular weight (Mw; >1 kDa) peptides using various types of amino acids (AAs), including proteinogenic/natural and nonnatural AAs. This advancement helps in obtaining peptides with improved stability, cell membrane permeability, and/or target-binding affinity. However, drug-drug interaction (DDI) information for these peptides remains scarce. Therefore, we focused on relatively high Mw peptides to examine their potential in inhibiting liver transporters, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, P-glycoprotein, and breast cancer resistant protein (BCRP) in vitro. We addressed the inhibitory effects of various types of cyclic peptides containing non-natural AAs and cell-penetrating peptides composed of proteinogenic/natural AAs. Our results demonstrated that several peptides inhibited transport activities, indicating that they can potentially cause DDI. We further evaluated the relationship between their inhibition potency and physicochemical properties (Mw and hydrophobicity or charge of the constituting AA) to characterize the specific physicochemical properties contributing to their inhibition potency. The hydrophobic AA contents of the peptides correlated with the inhibition potencies for all four transporters. Our findings demonstrate the transporter-mediated DDI potential of peptides and the necessity of their evaluation for drug development.
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Affiliation(s)
- Rika Ishikawa
- Division of Medicinal Safety Science, National Institute of Health Sciences, Kawasaki, Kanagawa, 210-9501, Japan.
| | - Takashi Misawa
- Division of Organic Chemistry, National Institute of Health Sciences, Kawasaki, Kanagawa, 210-9501, Japan.
| | - Yosuke Demizu
- Division of Organic Chemistry, National Institute of Health Sciences, Kawasaki, Kanagawa, 210-9501, Japan.
| | - Yoshiro Saito
- Deputy Director General, National Institute of Health Sciences, Kawasaki, Kanagawa, 210-9501, Japan.
| | - Ruri Kikura-Hanajiri
- Division of Medicinal Safety Science, National Institute of Health Sciences, Kawasaki, Kanagawa, 210-9501, Japan.
| | - Kosuke Saito
- Division of Medicinal Safety Science, National Institute of Health Sciences, Kawasaki, Kanagawa, 210-9501, Japan
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Nagaya Y, Nozaki Y. In vitro-in vivo scaling of cytochrome P450-mediated metabolic clearance using a relative activity factor approach. Drug Metab Dispos 2025; 53:100065. [PMID: 40199158 DOI: 10.1016/j.dmd.2025.100065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 03/05/2025] [Accepted: 03/07/2025] [Indexed: 04/10/2025] Open
Abstract
Quantitative prediction of hepatic clearance is a key element in predicting the human pharmacokinetic profile in the nonclinical stages. In the present study, we focused on the major cytochrome P450 (P450) isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) and tested a relative activity factor (RAF) method to quantitatively predict in vivo hepatic intrinsic clearance (CLh,int,vivo) and fraction metabolized (fm) by the P450 isoforms directly from an in vitro recombinant P450 system. We selected multiple probe substrates for CYP1A2 (caffeine, tizanidine, phenacetin), CYP2C9 ((S)-acenocoumarol, glimepiride, lornoxicam, tolbutamide, (S)-warfarin), CYP2C19 ((S)-lansoprazole, omeprazole, pantoprazole), CYP2D6 (desipramine, metoprolol, nebivolol, tolterodine), and CYP3A4 (alprazolam, felodipine, midazolam, nisoldipine, sildenafil, triazolam) to calculate the representative RAF value for each P450 isoform based on the in vivo-to-in vitro clearance ratio of the multiple probe substrates. The most pronounced substrate dependency of the RAF values was noted for CYP3A4 (2698 [alprazolam] to 19073 [nisoldipine] pmol P450/kg). Using the geometric mean of the RAF values for each isoform, a within 3-fold prediction of the CLh,int,vivo was obtained for all the 11 test drugs, except glibenclamide, which is a known substrate of hepatic uptake transporters. The fm values of the responsible P450 isoform(s) could be well predicted for mexiletine, tamsulosin, risperidone, celecoxib, and glibenclamide. This simple, practical RAF method can be one of the useful nonclinical methods to estimate the CLh,int,vivo and fm mediated by the major P450 isoforms, which would promote earlier understanding of the impact of genetic polymorphisms and drug-drug interactions on the human pharmacokinetics of the substrate compounds. SIGNIFICANCE STATEMENT: The relative activity factor method has been used for extrapolating in vitro clearance from recombinant systems to liver microsomes, but this study utilized this method to predict in vivo hepatic clearance and fraction metabolized values. By applying relative activity factor values obtained from multiple probe substrates, this study was able to quantitatively predict the in vivo clearances mediated by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. This simple, practical method will help optimize metabolic clearances via the major cytochrome P450 isoforms in the nonclinical stages.
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Affiliation(s)
- Yoko Nagaya
- Global Drug Metabolism and Pharmacokinetics, Eisai Co, Ltd, Ibaraki, Japan.
| | - Yoshitane Nozaki
- Global Drug Metabolism and Pharmacokinetics, Eisai Co, Ltd, Ibaraki, Japan
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6
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Radhakrishnan A, Shanmukhan NK, Samuel LC. Pharmacogenomics influence on MDR1-associated cancer resistance and innovative drug delivery approaches: advancing precision oncology. Med Oncol 2025; 42:67. [PMID: 39913003 DOI: 10.1007/s12032-025-02611-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 01/15/2025] [Indexed: 02/07/2025]
Abstract
Currently, there is a growing concern surrounding the treatment of cancer, a formidable disease. Pharmacogenomics and personalized medicine have emerged as significant areas of interest in cancer management. The efficacy of many cancer drugs is hindered by resistance mechanisms, particularly P-glycoprotein (P-gp) efflux, leading to reduced therapeutic outcomes. Efforts have intensified to inhibit P-gp efflux, thereby enhancing the effectiveness of resistant drugs. P-gp, a member of the ATP-binding cassette (ABC) superfamily, specifically the multidrug resistance (MDR)/transporter associated with antigen processing (TAP) sub-family B, member 1, utilizes energy derived from ATP hydrolysis to drive efflux. This review focuses on genetic polymorphisms associated with P-gp efflux and explores various novel pharmaceutical strategies to address this challenge. These strategies encompass SEDDS/SNEDDS, liposomes, immunoliposomes, solid lipid nanoparticles, lipid core nanocapsules, microemulsions, dendrimers, hydrogels, polymer-drug conjugates, and polymeric nanoparticles. The article aims to elucidate the interplay between pharmacogenomics, P-gp-mediated drug resistance in cancer, and formulation strategies to improve cancer therapy by tailoring formulations to genetically susceptible patients.
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Affiliation(s)
- Arun Radhakrishnan
- Department of Pharmaceutics, JKKN College of Pharmacy, Kumarapalayam, Tamil Nadu, 638183, India.
| | - Nikhitha K Shanmukhan
- Department of Pharmaceutics, JKKN College of Pharmacy, Kumarapalayam, Tamil Nadu, 638183, India
| | - Linda Christabel Samuel
- Department of Conservative Dentistry and Endodontics, JKKN Dental College and Hospitals, Kumarapalayam, 638183, India
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7
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Russell LE, Yadav J, Maldonato BJ, Chien HC, Zou L, Vergara AG, Villavicencio EG. Transporter-mediated drug-drug interactions: regulatory guidelines, in vitro and in vivo methodologies and translation, special populations, and the blood-brain barrier. Drug Metab Rev 2024:1-28. [PMID: 38967415 DOI: 10.1080/03602532.2024.2364591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 05/31/2024] [Indexed: 07/06/2024]
Abstract
This review, part of a special issue on drug-drug interactions (DDIs) spearheaded by the International Society for the Study of Xenobiotics (ISSX) New Investigators, explores the critical role of drug transporters in absorption, disposition, and clearance in the context of DDIs. Over the past two decades, significant advances have been made in understanding the clinical relevance of these transporters. Current knowledge on key uptake and efflux transporters that affect drug disposition and development is summarized. Regulatory guidelines from the FDA, EMA, and PMDA that inform the evaluation of potential transporter-mediated DDIs are discussed in detail. Methodologies for preclinical and clinical testing to assess potential DDIs are reviewed, with an emphasis on the utility of physiologically based pharmacokinetic (PBPK) modeling. This includes the application of relative abundance and expression factors to predict human pharmacokinetics (PK) using preclinical data, integrating the latest regulatory guidelines. Considerations for assessing transporter-mediated DDIs in special populations, including pediatric, hepatic, and renal impairment groups, are provided. Additionally, the impact of transporters at the blood-brain barrier (BBB) on the disposition of CNS-related drugs is explored. Enhancing the understanding of drug transporters and their role in drug disposition and toxicity can improve efficacy and reduce adverse effects. Continued research is essential to bridge remaining gaps in knowledge, particularly in comparison with cytochrome P450 (CYP) enzymes.
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Affiliation(s)
- Laura E Russell
- Department of Quantitative, Translational, and ADME Sciences, AbbVie Inc, North Chicago, IL, USA
| | - Jaydeep Yadav
- Department of Pharmacokinetics, Dynamics, Metabolism, and Bioanalytics, Merck & Co., Inc, Boston, MA, USA
| | - Benjamin J Maldonato
- Department of Nonclinical Development and Clinical Pharmacology, Revolution Medicines, Inc, Redwood City, CA, USA
| | - Huan-Chieh Chien
- Department of Pharmacokinetics and Drug Metabolism, Amgen Inc, South San Francisco, CA, USA
| | - Ling Zou
- Department of Pharmacokinetics and Drug Metabolism, Amgen Inc, South San Francisco, CA, USA
| | - Ana G Vergara
- Department of Pharmacokinetics, Dynamics, Metabolism, and Bioanalytics, Merck & Co., Inc, Rahway, NJ, USA
| | - Erick G Villavicencio
- Department of Biology-Discovery, Imaging and Functional Genomics, Merck & Co., Inc, Rahway, NJ, USA
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8
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Bechtold BJ, Lynch KD, Oyanna VO, Call MR, Graf TN, Oberlies NH, Clarke JD. Rifampin- and Silymarin-Mediated Pharmacokinetic Interactions of Exogenous and Endogenous Substrates in a Transgenic OATP1B Mouse Model. Mol Pharm 2024; 21:2284-2297. [PMID: 38529622 PMCID: PMC11073900 DOI: 10.1021/acs.molpharmaceut.3c01088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the SLCO gene family of the solute carrier superfamily, are involved in the disposition of many exogenous and endogenous compounds. Preclinical rodent models help assess risks of pharmacokinetic interactions, but interspecies differences in transporter orthologs and expression limit direct clinical translation. An OATP1B transgenic mouse model comprising a rodent Slco1a/1b gene cluster knockout and human SLCO1B1 and SLCO1B3 gene insertions provides a potential physiologically relevant preclinical tool to predict pharmacokinetic interactions. Pharmacokinetics of exogenous probe substrates, pitavastatin and pravastatin, and endogenous OATP1B biomarkers, coproporphyrin-I and coproporphyrin-III, were determined in the presence and absence of known OATP/Oatp inhibitors, rifampin or silymarin (an extract of milk thistle [Silybum marianum]), in wild-type FVB mice and humanized OATP1B mice. Rifampin increased exposure of pitavastatin (4.6- and 2.8-fold), pravastatin (3.6- and 2.2-fold), and coproporphyrin-III (1.6- and 2.1-fold) in FVB and OATP1B mice, respectively, but increased coproporphyrin-I AUC0-24h only (1.8-fold) in the OATP1B mice. Silymarin did not significantly affect substrate AUC, likely because the silymarin flavonolignan concentrations were at or below their reported IC50 values for the relevant OATPs/Oatps. Silymarin increased the Cmax of pitavastatin 2.7-fold and pravastatin 1.9-fold in the OATP1B mice. The data of the OATP1B mice were similar to those of the pitavastatin and pravastatin clinical data; however, the FVB mice data more closely recapitulated pitavastatin clinical data than the data of the OATP1B mice, suggesting that the OATP1B mice are a reasonable, though costly, preclinical strain for predicting pharmacokinetic interactions when doses are optimized to achieve clinically relevant plasma concentrations.
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Affiliation(s)
- Baron J. Bechtold
- Department of Pharmaceutical Sciences, Washington State University, 412 E. Spokane Falls Blvd., Spokane, Washington 99202, United States
| | - Katherine D. Lynch
- Department of Pharmaceutical Sciences, Washington State University, 412 E. Spokane Falls Blvd., Spokane, Washington 99202, United States
| | - Victoria O. Oyanna
- Department of Pharmaceutical Sciences, Washington State University, 412 E. Spokane Falls Blvd., Spokane, Washington 99202, United States
| | - M. Ridge Call
- Department of Pharmaceutical Sciences, Washington State University, 412 E. Spokane Falls Blvd., Spokane, Washington 99202, United States
| | - Tyler N. Graf
- Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, North Carolina, 27412, United States
| | - Nicholas H. Oberlies
- Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, North Carolina, 27412, United States
| | - John D. Clarke
- Department of Pharmaceutical Sciences, Washington State University, 412 E. Spokane Falls Blvd., Spokane, Washington 99202, United States
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Tang L, Ye Y, Ji J, Wang JS, Huang Z, Sun J, Sheng L, Sun X. PI3K/Akt/FoxO Pathway Mediates Antagonistic Toxicity in HepG2 Cells Coexposed to Deoxynivalenol and Enniatins. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:8214-8224. [PMID: 38557103 DOI: 10.1021/acs.jafc.4c01888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
The emerging mycotoxins enniatins (ENNs) and the traditional mycotoxin deoxynivalenol (DON) often co-contaminate various grain raw materials and foods. While the liver is their common target organ, the mechanism of their combined effect remains unclear. In this study, the combined cytotoxic effects of four ENNs (ENA, ENA1, ENB, and ENB1) with DON and their mechanisms were investigated using the HepG2 cell line. Additionally, a population exposure risk assessment of these mycotoxins was performed by using in vitro experiments and computer simulations. The results showed that only ENA at 1/4 IC50 and ENB1 at 1/8 IC50 coexposed with DON showed an additive effect, while ENB showed the strongest antagonism at IC50 (CI = 3.890). Co-incubation of ENNs regulated the signaling molecule levels which were disrupted by DON. Transcriptome analysis showed that ENB (IC50) up-regulated the PI3K/Akt/FoxO signaling pathway and inhibited the expression of apoptotic genes (Bax, P53, Caspase 3, etc.) via phosphorylation of FoxO, thereby reducing the cytotoxic effects caused by DON. Both types of mycotoxins posed serious health risks, and the cumulative risk of coexposure was particularly important for emerging mycotoxins.
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Affiliation(s)
- Luyao Tang
- School of Food Science and Technology, International Joint Laboratory on Food Safety, Synergetic Innovation Center of Food Safety and Quality Control, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
- Yixing Institute of Food and Biotechnology Co., Ltd, Yixing, Jiangsu 214200, PR China
| | - Yongli Ye
- School of Food Science and Technology, International Joint Laboratory on Food Safety, Synergetic Innovation Center of Food Safety and Quality Control, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
- Yixing Institute of Food and Biotechnology Co., Ltd, Yixing, Jiangsu 214200, PR China
| | - Jian Ji
- School of Food Science and Technology, International Joint Laboratory on Food Safety, Synergetic Innovation Center of Food Safety and Quality Control, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
- Yixing Institute of Food and Biotechnology Co., Ltd, Yixing, Jiangsu 214200, PR China
| | - Jia-Sheng Wang
- Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, Georgia 30602, United States
| | - Zhicong Huang
- Food and Drug Administration, Zhongshan City West District Street, Zhongshan, Guangdong 528401, PR China
| | - Jiadi Sun
- School of Food Science and Technology, International Joint Laboratory on Food Safety, Synergetic Innovation Center of Food Safety and Quality Control, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
- Yixing Institute of Food and Biotechnology Co., Ltd, Yixing, Jiangsu 214200, PR China
| | - Lina Sheng
- School of Food Science and Technology, International Joint Laboratory on Food Safety, Synergetic Innovation Center of Food Safety and Quality Control, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
- Yixing Institute of Food and Biotechnology Co., Ltd, Yixing, Jiangsu 214200, PR China
| | - Xiulan Sun
- School of Food Science and Technology, International Joint Laboratory on Food Safety, Synergetic Innovation Center of Food Safety and Quality Control, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
- Yixing Institute of Food and Biotechnology Co., Ltd, Yixing, Jiangsu 214200, PR China
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10
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Gulnaz A, Lee KR, Kang MJ, Chang JE, Chae YJ. Roles of breast cancer resistance protein and organic anion transporting polypeptide 2B1 in gastrointestinal toxicity induced by SN-38 under inflammatory conditions. Toxicol Lett 2024; 394:57-65. [PMID: 38423481 DOI: 10.1016/j.toxlet.2024.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 01/29/2024] [Accepted: 02/25/2024] [Indexed: 03/02/2024]
Abstract
Drug transporters are among the factors that determine the pharmacokinetic profiles after drug administration. In this study, we investigated the roles of drug transporters involved in transport of SN-38, which is an active metabolite of irinotecan, in the intestine under inflammatory conditions in vitro and determined their functional consequences. The expression alterations of breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 2B1 were determined at the mRNA and protein levels, and the subsequent functional alterations were evaluated via an accumulation study with the representative transporter substrates [prazosin and dibromofluorescein (DBF)] and SN-38. We also determined the cytotoxicity of SN-38 under inflammatory conditions. Decreased BCRP expression and increased OATP2B1 expression were observed under inflammatory conditions in vitro, which led to altered accumulation profiles of prazosin, DBF, and SN-38, and the subsequent cytotoxic profiles of SN-38. Treatment with rifampin or novobiocin supported the significant roles of BCRP and OATP2B1 in the transport and cytotoxic profile of SN-38. Collectively, these results suggest that BCRP and OATP2B1 are involved in the increased cytotoxicity of SN-38 under inflammatory conditions in vitro. Further comprehensive research is warranted to completely understand SN-38-induced gastrointestinal cytotoxicity and aid in the successful treatment of cancer with irinotecan.
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Affiliation(s)
- Aneela Gulnaz
- College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea
| | - Kyeong-Ryoon Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea; Department of Bioscience, University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Min-Ji Kang
- College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea
| | - Ji-Eun Chang
- College of Pharmacy, Dongduk Women's University, Seoul 02748, Republic of Korea
| | - Yoon-Jee Chae
- College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea; Research Institute of Pharmaceutical Sciences, Woosuk University, Wanju 55338, Republic of Korea.
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11
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Shi Y, Reker D, Byrne JD, Kirtane AR, Hess K, Wang Z, Navamajiti N, Young CC, Fralish Z, Zhang Z, Lopes A, Soares V, Wainer J, von Erlach T, Miao L, Langer R, Traverso G. Screening oral drugs for their interactions with the intestinal transportome via porcine tissue explants and machine learning. Nat Biomed Eng 2024; 8:278-290. [PMID: 38378821 DOI: 10.1038/s41551-023-01128-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 10/01/2023] [Indexed: 02/22/2024]
Abstract
In vitro systems that accurately model in vivo conditions in the gastrointestinal tract may aid the development of oral drugs with greater bioavailability. Here we show that the interaction profiles between drugs and intestinal drug transporters can be obtained by modulating transporter expression in intact porcine tissue explants via the ultrasound-mediated delivery of small interfering RNAs and that the interaction profiles can be classified via a random forest model trained on the drug-transporter relationships. For 24 drugs with well-characterized drug-transporter interactions, the model achieved 100% concordance. For 28 clinical drugs and 22 investigational drugs, the model identified 58 unknown drug-transporter interactions, 7 of which (out of 8 tested) corresponded to drug-pharmacokinetic measurements in mice. We also validated the model's predictions for interactions between doxycycline and four drugs (warfarin, tacrolimus, digoxin and levetiracetam) through an ex vivo perfusion assay and the analysis of pharmacologic data from patients. Screening drugs for their interactions with the intestinal transportome via tissue explants and machine learning may help to expedite drug development and the evaluation of drug safety.
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Affiliation(s)
- Yunhua Shi
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Daniel Reker
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - James D Byrne
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
| | - Ameya R Kirtane
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kaitlyn Hess
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Zhuyi Wang
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Natsuda Navamajiti
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biomedical Engineering, Chulalongkorn University, Bangkok, Thailand
| | - Cameron C Young
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Zachary Fralish
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Zilu Zhang
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Aaron Lopes
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Vance Soares
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Jacob Wainer
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Thomas von Erlach
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Lei Miao
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Robert Langer
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Giovanni Traverso
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
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12
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Storelli F, Ladumor MK, Liang X, Lai Y, Chothe PP, Enogieru OJ, Evers R, Unadkat JD. Toward improved predictions of pharmacokinetics of transported drugs in hepatic impairment: Insights from the extended clearance model. CPT Pharmacometrics Syst Pharmacol 2024; 13:118-131. [PMID: 37833845 PMCID: PMC10787213 DOI: 10.1002/psp4.13062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/04/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatic impairment (HI) moderately (<5-fold) affects the systemic exposure (i.e., area under the plasma concentration-time curve [AUC]) of drugs that are substrates of the hepatic sinusoidal organic anion transporting polypeptide (OATP) transporters and are excreted unchanged in the bile and/or urine. However, the effect of HI on their AUC is much greater (>10-fold) for drugs that are also substrates of cytochrome P450 (CYP) 3A enzymes. Using the extended clearance model, through simulations, we identified the ratio of sinusoidal efflux clearance (CL) over the sum of metabolic and biliary CLs as important in predicting the impact of HI on the AUC of dual OATP/CYP3A substrates. Because HI may reduce hepatic CYP3A-mediated CL to a greater extent than biliary efflux CL, the greater the contribution of the former versus the latter, the greater the impact of HI on drug AUC ratio (AUCRHI ). Using physiologically-based pharmacokinetic modeling and simulation, we predicted relatively well the AUCRHI of OATP substrates that are not significantly metabolized (pitavastatin, rosuvastatin, valsartan, and gadoxetic acid). However, there was a trend toward underprediction of the AUCRHI of the dual OATP/CYP3A4 substrates fimasartan and atorvastatin. These predictions improved when the sinusoidal efflux CL of these two drugs was increased in healthy volunteers (i.e., before incorporating the effect of HI), and by modifying the directionality of its modulation by HI (i.e., increase or decrease). To accurately predict the effect of HI on AUC of hepatobiliary cleared drugs it is important to accurately predict all hepatobiliary pathways, including sinusoidal efflux CL.
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Affiliation(s)
- Flavia Storelli
- Department of PharmaceuticsUniversity of WashingtonSeattleWashingtonUSA
| | - Mayur K. Ladumor
- Department of PharmaceuticsUniversity of WashingtonSeattleWashingtonUSA
| | - Xiaomin Liang
- Drug Metabolism, Gilead Sciences Inc.Foster CityCaliforniaUSA
| | - Yurong Lai
- Drug Metabolism, Gilead Sciences Inc.Foster CityCaliforniaUSA
| | - Paresh P. Chothe
- Global Drug Metabolism and Pharmacokinetics, Takeda Development Center Americas, Inc.LexingtonMassachusettsUSA
| | | | - Raymond Evers
- Preclinical Sciences and Translational Safety, Janssen Research & Development, LLCSpring HousePennsylvaniaUSA
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13
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Rowland M, Weiss M, Pang KS. Kirchhoff's Laws and Hepatic Clearance, Well-Stirred Model - Is There Common Ground? Drug Metab Dispos 2023; 51:1451-1454. [PMID: 37562956 DOI: 10.1124/dmd.123.001300] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 07/24/2023] [Accepted: 07/28/2023] [Indexed: 08/12/2023] Open
Abstract
Clearance concepts are extensively applied in drug development and drug therapy. The well-stirred model (WSM) of hepatic elimination is the most widely adopted physiologic model in pharmacokinetics owing to its simplicity. A common feature of this organ model is its use to relate hepatic clearance of a compound to the physiologic variables: organ blood flow rate, binding within blood, and hepatocellular metabolic and excretory activities. Recently, Kirchhoff's laws of electrical network have been applied to organ clearance (Pachter et al., 2022; Benet and Sodhi, 2023) with the claim that they yield the same equation for hepatic clearance as the WSM, and that the equation is independent of a mechanistic model. This commentary analyzes this claim and shows that implicit in the application of Kirchhoff's approaches are the same assumptions as those of the WSM. Concern is also expressed in the interpretation of permeability or transport parameters and related equations, as well as the inappropriateness of the corresponding equation defining hepatic clearance. There is no value, and some dangers, in applying Kirchhoff's electrical laws to organ clearance. SIGNIFICANCE STATEMENT: This commentary refutes this claim by Pachter et al. (2022), and Benet and Sodhi, (2023), who suggest that the well-stirred model (WSM) of hepatic elimination, the most widely applied physiologic model of hepatic clearance, provides the same equation as Kirchhoff's laws of electrical network that is independent of a physiologic model. A careful review shows that the claim is groundless and fraught with errors. We conclude that there is no place for the application of Kirchhoff's laws to organ clearance models.
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Affiliation(s)
- Malcolm Rowland
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (M.R.); Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany (M.W.); and Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada (K.S.P.)
| | - Michael Weiss
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (M.R.); Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany (M.W.); and Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada (K.S.P.)
| | - K Sandy Pang
- Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (M.R.); Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany (M.W.); and Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada (K.S.P.)
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14
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Lai Y, Zhong XB. Special Section on Mechanism-Based Predictive Methods in Drug Discovery and Development-Editorial. Drug Metab Dispos 2023; 51:1064-1066. [PMID: 37586888 DOI: 10.1124/dmd.123.001456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 07/07/2023] [Indexed: 08/18/2023] Open
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15
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Gyimesi G, Hediger MA. Transporter-Mediated Drug Delivery. Molecules 2023; 28:molecules28031151. [PMID: 36770817 PMCID: PMC9919865 DOI: 10.3390/molecules28031151] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/12/2023] [Accepted: 01/18/2023] [Indexed: 01/27/2023] Open
Abstract
Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It was recognized early on that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical compositions has recently been used as a means to enhance their targeting and absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters.
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16
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Vijaywargi G, Kollipara S, Ahmed T, Chachad S. Predicting transporter mediated drug-drug interactions via static and dynamic physiologically based pharmacokinetic modeling: A comprehensive insight on where we are now and the way forward. Biopharm Drug Dispos 2022. [PMID: 36413625 DOI: 10.1002/bdd.2339] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 10/07/2022] [Accepted: 11/04/2022] [Indexed: 11/23/2022]
Abstract
The greater utilization and acceptance of physiologically-based pharmacokinetic (PBPK) modeling to evaluate the potential metabolic drug-drug interactions is evident by the plethora of literature, guidance's, and regulatory dossiers available in the literature. In contrast, it is not widely used to predict transporter-mediated DDI (tDDI). This is attributed to the unavailability of accurate transporter tissue expression levels, the absence of accurate in vitro to in vivo extrapolations (IVIVE), enzyme-transporter interplay, and a lack of specific probe substrates. Additionally, poor understanding of the inhibition/induction mechanisms coupled with the inability to determine unbound concentrations at the interaction site made tDDI assessment challenging. Despite these challenges, continuous improvements in IVIVE approaches enabled accurate tDDI predictions. Furthermore, the necessity of extrapolating tDDI's to special (pediatrics, pregnant, geriatrics) and diseased (renal, hepatic impaired) populations is gaining impetus and is encouraged by regulatory authorities. This review aims to visit the current state-of-the-art and summarizes contemporary knowledge on tDDI predictions. The current understanding and ability of static and dynamic PBPK models to predict tDDI are portrayed in detail. Peer-reviewed transporter abundance data in special and diseased populations from recent publications were compiled, enabling direct input into modeling tools for accurate tDDI predictions. A compilation of regulatory guidance's for tDDI's assessment and success stories from regulatory submissions are presented. Future perspectives and challenges of predicting tDDI in terms of in vitro system considerations, endogenous biomarkers, the use of empirical scaling factors, enzyme-transporter interplay, and acceptance criteria for model validation to meet the regulatory expectations were discussed.
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Affiliation(s)
- Gautam Vijaywargi
- Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India
| | - Sivacharan Kollipara
- Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India
| | - Tausif Ahmed
- Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India
| | - Siddharth Chachad
- Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India
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17
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Jilek JL, Frost KL, Marie S, Myers CM, Goedken M, Wright SH, Cherrington NJ. Attenuated Ochratoxin A Transporter Expression in a Mouse Model of Nonalcoholic Steatohepatitis Protects against Proximal Convoluted Tubule Toxicity. Drug Metab Dispos 2022; 50:1389-1395. [PMID: 34921099 PMCID: PMC9513848 DOI: 10.1124/dmd.121.000451] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 12/16/2021] [Indexed: 12/16/2022] Open
Abstract
Ochratoxin A (OTA) is an abundant mycotoxin, yet the toxicological impact of its disposition is not well studied. OTA is an organic anion transporter (OAT) substrate primarily excreted in urine despite a long half-life and extensive protein binding. Altered renal transporter expression during disease, including nonalcoholic steatohepatitis (NASH), may influence response to OTA exposure, but the impact of NASH on OTA toxicokinetics, tissue distribution, and associated nephrotoxicity is unknown. By inducing NASH in fast food-dieted/thioacetamide-exposed mice, we evaluated the effect of NASH on a bolus OTA exposure (12.5 mg/kg by mouth) after 3 days. NASH mice presented with less gross toxicity (44% less body weight loss), and kidney and liver weights of NASH mice were 11% and 24% higher, respectively, than healthy mice. Organ and body weight changes coincided with reduced renal proximal tubule cells vacuolation, degeneration, and necrosis, though no OTA-induced hepatic lesions were found. OTA systemic exposure in NASH mice increased modestly from 5.65 ± 1.10 to 7.95 ± 0.61 mg*h/ml per kg BW, and renal excretion increased robustly from 5.55% ± 0.37% to 13.11% ± 3.10%, relative to healthy mice. Total urinary excretion of OTA increased from 24.41 ± 1.74 to 40.07 ± 9.19 µg in NASH mice, and kidney-bound OTA decreased by ∼30%. Renal OAT isoform expression (OAT1-5) in NASH mice decreased by ∼50% with reduced OTA uptake by proximal convoluted cells. These data suggest that NASH-induced OAT transporter reductions attenuate renal secretion and reabsorption of OTA, increasing OTA urinary excretion and reducing renal exposure, thereby reducing nephrotoxicity in NASH. SIGNIFICANCE STATEMENT: These data suggest a disease-mediated transporter mechanism of altered tissue-specific toxicity after mycotoxin exposure, despite minimal systemic changes to ochratoxin A (OTA) concentrations. Further studies are warranted to evaluate the clinical relevance of this functional model and the potential effect of human nonalcoholic steatohepatitis on OTA and other organic anion substrate toxicity.
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Affiliation(s)
- Joseph L Jilek
- Department of Pharmacology and Toxicology, University of Arizona, College of Pharmacy, Tucson, Arizona (J.L.J., K.L.F., S.M., C.M.M., N.J.C.); Rutgers Translational Sciences, Rutgers University, Piscataway, New Jersey (M.G.); and Department of Physiology, University of Arizona, College of Medicine, Tucson, Arizona (S.H.W.)
| | - Kayla L Frost
- Department of Pharmacology and Toxicology, University of Arizona, College of Pharmacy, Tucson, Arizona (J.L.J., K.L.F., S.M., C.M.M., N.J.C.); Rutgers Translational Sciences, Rutgers University, Piscataway, New Jersey (M.G.); and Department of Physiology, University of Arizona, College of Medicine, Tucson, Arizona (S.H.W.)
| | - Solène Marie
- Department of Pharmacology and Toxicology, University of Arizona, College of Pharmacy, Tucson, Arizona (J.L.J., K.L.F., S.M., C.M.M., N.J.C.); Rutgers Translational Sciences, Rutgers University, Piscataway, New Jersey (M.G.); and Department of Physiology, University of Arizona, College of Medicine, Tucson, Arizona (S.H.W.)
| | - Cassandra M Myers
- Department of Pharmacology and Toxicology, University of Arizona, College of Pharmacy, Tucson, Arizona (J.L.J., K.L.F., S.M., C.M.M., N.J.C.); Rutgers Translational Sciences, Rutgers University, Piscataway, New Jersey (M.G.); and Department of Physiology, University of Arizona, College of Medicine, Tucson, Arizona (S.H.W.)
| | - Michael Goedken
- Department of Pharmacology and Toxicology, University of Arizona, College of Pharmacy, Tucson, Arizona (J.L.J., K.L.F., S.M., C.M.M., N.J.C.); Rutgers Translational Sciences, Rutgers University, Piscataway, New Jersey (M.G.); and Department of Physiology, University of Arizona, College of Medicine, Tucson, Arizona (S.H.W.)
| | - Stephen H Wright
- Department of Pharmacology and Toxicology, University of Arizona, College of Pharmacy, Tucson, Arizona (J.L.J., K.L.F., S.M., C.M.M., N.J.C.); Rutgers Translational Sciences, Rutgers University, Piscataway, New Jersey (M.G.); and Department of Physiology, University of Arizona, College of Medicine, Tucson, Arizona (S.H.W.)
| | - Nathan J Cherrington
- Department of Pharmacology and Toxicology, University of Arizona, College of Pharmacy, Tucson, Arizona (J.L.J., K.L.F., S.M., C.M.M., N.J.C.); Rutgers Translational Sciences, Rutgers University, Piscataway, New Jersey (M.G.); and Department of Physiology, University of Arizona, College of Medicine, Tucson, Arizona (S.H.W.)
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18
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The next frontier in ADME science: Predicting transporter-based drug disposition, tissue concentrations and drug-drug interactions in humans. Pharmacol Ther 2022; 238:108271. [DOI: 10.1016/j.pharmthera.2022.108271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/05/2022] [Accepted: 08/17/2022] [Indexed: 12/25/2022]
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19
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Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B 2022; 12:3049-3062. [PMID: 35865092 PMCID: PMC9293739 DOI: 10.1016/j.apsb.2022.02.002] [Citation(s) in RCA: 620] [Impact Index Per Article: 206.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 02/03/2022] [Accepted: 02/06/2022] [Indexed: 12/14/2022] Open
Abstract
Ninety percent of clinical drug development fails despite implementation of many successful strategies, which raised the question whether certain aspects in target validation and drug optimization are overlooked? Current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity-relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity. We propose structure‒tissue exposure/selectivity-activity relationship (STAR) to improve drug optimization, which classifies drug candidates based on drug's potency/selectivity, tissue exposure/selectivity, and required dose for balancing clinical efficacy/toxicity. Class I drugs have high specificity/potency and high tissue exposure/selectivity, which needs low dose to achieve superior clinical efficacy/safety with high success rate. Class II drugs have high specificity/potency and low tissue exposure/selectivity, which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated. Class III drugs have relatively low (adequate) specificity/potency but high tissue exposure/selectivity, which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked. Class IV drugs have low specificity/potency and low tissue exposure/selectivity, which achieves inadequate efficacy/safety, and should be terminated early. STAR may improve drug optimization and clinical studies for the success of clinical drug development.
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Affiliation(s)
- Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Wei Gao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Hongxiang Hu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Simon Zhou
- Translational Development and Clinical Pharmacology, Bristol Meyer Squibb Company, Summit, NJ, 07920, USA
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20
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Ahmed Juvale II, Abdul Hamid AA, Abd Halim KB, Che Has AT. P-glycoprotein: new insights into structure, physiological function, regulation and alterations in disease. Heliyon 2022; 8:e09777. [PMID: 35789865 PMCID: PMC9249865 DOI: 10.1016/j.heliyon.2022.e09777] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 02/04/2022] [Accepted: 06/17/2022] [Indexed: 01/01/2023] Open
Abstract
The multidrug resistance phenomenon presents a major threat to the pharmaceutical industry. This resistance is a common occurrence in several diseases and is mediated by multidrug transporters that actively pump substances out of the cell and away from their target regions. The most well-known multidrug transporter is the P-glycoprotein transporter. The binding sites within P-glycoprotein can accommodate a variety of compounds with diverse structures. Hence, numerous drugs are P-glycoprotein substrates, with new ones being identified every day. For many years, the mechanisms of action of P-glycoprotein have been shrouded in mystery, and scientists have only recently been able to elucidate certain structural and functional aspects of this protein. Although P-glycoprotein is highly implicated in multidrug resistant diseases, this transporter also performs various physiological roles in the human body and is expressed in several tissues, including the brain, kidneys, liver, gastrointestinal tract, testis, and placenta. The expression levels of P-glycoprotein are regulated by different enzymes, inflammatory mediators and transcription factors; alterations in which can result in the generation of a disease phenotype. This review details the discovery, the recently proposed structure and the regulatory functions of P-glycoprotein, as well as the crucial role it plays in health and disease.
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Affiliation(s)
- Iman Imtiyaz Ahmed Juvale
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian, Kota Bharu, 16150, Kelantan, Malaysia
| | - Azzmer Azzar Abdul Hamid
- Department of Biotechnology, Kulliyyah of Science, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Bandar Indera Mahkota, 25200, Kuantan, Pahang, Malaysia
| | - Khairul Bariyyah Abd Halim
- Research Unit for Bioinformatics and Computational Biology (RUBIC), Kulliyyah of Science, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Bandar Indera Mahkota, 25200, Kuantan, Pahang, Malaysia
| | - Ahmad Tarmizi Che Has
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian, Kota Bharu, 16150, Kelantan, Malaysia
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21
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Williamson B, McMurray L, Boyd S, Collingwood O, McLean N, Winter-Holt J, Chan C, Xue A, McCoull W. Identification and Strategies to Mitigate High Total Clearance of Benzylamine-Substituted Biphenyl Ring Systems. Mol Pharm 2022; 19:2115-2132. [PMID: 35533086 DOI: 10.1021/acs.molpharmaceut.2c00014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
For most oral small-molecule projects within drug discovery, the extent and duration of the effect are influenced by the total clearance of the compound; hence, designing compounds with low clearance remains a key focus to help enable sufficient protein target engagement. Comprehensive understanding and accurate prediction of animal clearance and pharmacokinetics provides confidence that the same can be observed for human. During a MERTK inhibitor lead optimization project, a series containing a biphenyl ring system with benzylamine meta-substitution on one phenyl and nitrogen inclusion as the meta atom on the other ring demonstrated multiple routes of compound elimination in rats. Here, we describe the identification of a structural pharmacophore involving two key interactions observed for both the MERTK program and an additional internal project. Four strategies to mitigate these clearance liabilities were identified and systematically investigated. We provide evidence that disruption of at least one of the interactions led to a significant reduction in CL that was subsequently predicted from rat hepatocytes using in vitro/in vivo extrapolation and the well-stirred scaling method. These tactics will likely be of general utility to the medicinal chemistry and DMPK community during compound optimization when similar issues are encountered for biphenyl benzylamines.
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Affiliation(s)
- Beth Williamson
- Drug Metabolism and Pharmacokinetics, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Lindsay McMurray
- Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Scott Boyd
- Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Olga Collingwood
- Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Neville McLean
- Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Jon Winter-Holt
- Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Christina Chan
- Drug Metabolism and Pharmacokinetics, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Aixiang Xue
- R&D Clinical Pharmacology and Safety Sciences, AstraZeneca, Waltham 02451, United States
| | - William McCoull
- Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
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22
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Gao W, Hu H, Dai L, He M, Yuan H, Zhang H, Liao J, Wen B, Li Y, Palmisano M, Traore MDM, Zhou S, Sun D. Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety. Acta Pharm Sin B 2022; 12:2462-2478. [PMID: 35646532 PMCID: PMC9136610 DOI: 10.1016/j.apsb.2022.02.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/23/2022] [Accepted: 02/12/2022] [Indexed: 11/17/2022] Open
Abstract
Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.
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Affiliation(s)
- Wei Gao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hongxiang Hu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lipeng Dai
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Miao He
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hebao Yuan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Huixia Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jinhui Liao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Bo Wen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yan Li
- Translational Development and Clinical Pharmacology, Bristol Myers Squibb, Summit, NJ 07920, USA
| | - Maria Palmisano
- Translational Development and Clinical Pharmacology, Bristol Myers Squibb, Summit, NJ 07920, USA
| | - Mohamed Dit Mady Traore
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Simon Zhou
- Translational Development and Clinical Pharmacology, Bristol Myers Squibb, Summit, NJ 07920, USA
| | - Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
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23
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Mao J, Li Q, Li P, Qin W, Chen B, Zhong M. Evaluation and Application of Population Pharmacokinetic Models for Identifying Delayed Methotrexate Elimination in Patients With Primary Central Nervous System Lymphoma. Front Pharmacol 2022; 13:817673. [PMID: 35355729 PMCID: PMC8959905 DOI: 10.3389/fphar.2022.817673] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 02/14/2022] [Indexed: 11/30/2022] Open
Abstract
Objective: Several population pharmacokinetic (popPK) models have been developed to determine the sources of methotrexate (MTX) PK variability. It remains unknown if these published models are precise enough for use or if a new model needs to be built. The aims of this study were to 1) assess the predictability of published models and 2) analyze the potential risk factors for delayed MTX elimination. Methods: A total of 1458 MTX plasma concentrations, including 377 courses (1–17 per patient), were collected from 77 patients who were receiving high-dose MTX for the treatment of primary central nervous system lymphoma in Huashan Hospital. PopPK analysis was performed using the NONMEM® software package. Previously published popPK models were selected and rebuilt. A new popPK model was then constructed to screen potential covariates using a stepwise approach. The covariates were included based on the combination of theoretical mechanisms and data properties. Goodness-of-fit plots, bootstrap, and prediction- and simulation-based diagnostics were used to determine the stability and predictive performance of both the published and newly built models. Monte Carlo simulations were conducted to qualify the influence of risk factors on the incidence of delayed elimination. Results: Among the eight evaluated published models, none presented acceptable values of bias or inaccuracy. A two-compartment model was employed in the newly built model to describe the PK of MTX. The estimated mean clearance (CL/F) was 4.91 L h−1 (relative standard error: 3.7%). Creatinine clearance, albumin, and age were identified as covariates of MTX CL/F. The median and median absolute prediction errors of the final model were -10.2 and 36.4%, respectively. Results of goodness-of-fit plots, bootstrap, and prediction-corrected visual predictive checks indicated the high predictability of the final model. Conclusions: Current published models are not sufficiently reliable for cross-center use. The elderly patients and those with renal dysfunction, hypoalbuminemia are at higher risk of delayed elimination.
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Affiliation(s)
- Junjun Mao
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Qing Li
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China.,Department of Hematology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Pei Li
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China
| | - Weiwei Qin
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Bobin Chen
- Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China.,Department of Hematology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Mingkang Zhong
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
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24
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Consideration of Fractional Distribution Parameter f d in the Chen and Gross Method for Tissue-to-Plasma Partition Coefficients: Comparison of Several Methods. Pharm Res 2022; 39:463-479. [PMID: 35288804 PMCID: PMC9014445 DOI: 10.1007/s11095-022-03211-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/17/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE The tissue-to-plasma partition coefficient (Kp) describes the extent of tissue distribution in physiologically-based pharmacokinetic (PBPK) models. Constant-rate infusion studies are common for experimental determination of the steady-state Kp,ss, while the tissue-plasma concentration ratio (CT/Cp) in the terminal phase after intravenous doses is often utilized. The Chen and Gross (C&G) method converts a terminal slope CT/Cp to Kp,ss based on assumptions of perfusion-limited distribution in tissue-plasma equilibration. However, considering blood flow (QT) and apparent tissue permeability (fupPSin) in the rate of tissue distribution, this report extends the C&G method by utilizing a fractional distribution parameter (fd). METHODS Relevant PBPK equations for non-eliminating and eliminating organs along with lung and liver were derived for the conversion of CT/Cp values to Kp,ss. The relationships were demonstrated in rats with measured CT/Cp and Kp,ss values and the model-dependent fd for 8 compounds with a range of permeability coefficients. Several methods of assessing Kp were compared. RESULTS Utilizing fd in an extended C&G method, our estimations of Kp,ss from CT/Cp were improved, particularly for lower permeability compounds. However, four in silico methods for estimating Kp performed poorly across tissues in comparison with measured Kp values. Mathematical relationships between Kp and Kp,ss that are generally applicable for eliminating organs with tissue permeability limitations necessitates inclusion of an extraction ratio (ER) and fd. CONCLUSION Since many different types/sources of Kp are present in the literature and used in PBPK models, these perspectives and equations should provide better insights in measuring and interpreting Kp values in PBPK.
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25
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Kimoto E, Costales C, West MA, Bi YA, Vourvahis M, David Rodrigues A, Varma MVS. Biomarker-Informed Model-Based Risk Assessment of Organic Anion Transporting Polypeptide 1B Mediated Drug-Drug Interactions. Clin Pharmacol Ther 2021; 111:404-415. [PMID: 34605015 DOI: 10.1002/cpt.2434] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/15/2021] [Indexed: 11/08/2022]
Abstract
Quantitative prediction of drug-drug interactions (DDIs) involving organic anion transporting polypeptide (OATP)1B1/1B3 inhibition is limited by uncertainty in the translatability of experimentally determined in vitro inhibition potency (half-maximal inhibitory concentration (IC50 )). This study used an OATP1B endogenous biomarker-informed physiologically-based pharmacokinetic (PBPK) modeling approach to predict the effect of inhibitor drugs on the pharmacokinetics (PKs) of OATP1B substrates. Initial static analysis with about 42 inhibitor drugs, using in vitro IC50 values and unbound liver inlet concentrations (Iin,max,u ), suggested in vivo OATP1B inhibition risk for drugs with R-value (1+ Iin,max,u /IC50 ) above 1.5. A full-PBPK model accounting for transporter-mediated hepatic disposition was developed for coproporphyrin I (CP-I), an endogenous OATP1B biomarker. For several inhibitors (cyclosporine, diltiazem, fenebrutinib, GDC-0810, itraconazole, probenecid, and rifampicin at 3 different doses), PBPK models were developed and verified against available CP-I plasma exposure data to obtain in vivo OATP1B inhibition potency-which tend to be lower than the experimentally measured in vitro IC50 by about 2-fold (probenecid and rifampicin) to 37-fold (GDC-0810). Models verified with CP-I data are subsequently used to predict DDIs with OATP1B probe drugs, rosuvastatin and pitavastatin. The predicted and observed area under the plasma concentration-time curve ratios are within 20% error in 55% cases, and within 30% error in 89% cases. Collectively, this comprehensive study illustrates the adequacy and utility of endogenous biomarker-informed PBPK modeling in mechanistic understanding and quantitative predictions of OATP1B-mediated DDIs in drug development.
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Affiliation(s)
- Emi Kimoto
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
| | - Chester Costales
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
| | - Mark A West
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
| | - Yi-An Bi
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
| | - Manoli Vourvahis
- Clinical Pharmacology, Global Product Development, Pfizer Inc, New York, New York, USA
| | - A David Rodrigues
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
| | - Manthena V S Varma
- Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, Connecticut, USA
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26
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Truong VL, Jun M, Jeong WS. Phytochemical and Over-The-Counter Drug Interactions: Involvement of Phase I and II Drug-Metabolizing Enzymes and Phase III Transporters. J Med Food 2021; 24:786-805. [PMID: 34382862 DOI: 10.1089/jmf.2021.k.0003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Consumption of plant-derived natural products and over-the-counter (OTC) drugs is increasing on a global scale, and studies of phytochemical-OTC drug interactions are becoming more significant. The intake of dietary plants and herbs rich in phytochemicals may affect drug-metabolizing enzymes (DMEs) and transporters. These effects may lead to alterations in pharmacokinetics and pharmacodynamics of OTC drugs when concomitantly administered. Some phytochemical-drug interactions benefit patients through enhanced efficacy, but many interactions cause adverse effects. This review discusses possible mechanisms of phytochemical-OTC drug interactions mediated by phase I and II DMEs and phase III transporters. In addition, current information is summarized for interactions between phytochemicals derived from fruits, vegetables, and herbs and OTC drugs, and counseling is provided on appropriate and safe use of OTC drugs.
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Affiliation(s)
- Van-Long Truong
- Food and Bio-Industry Research Institute, School of Food Science and Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu, Korea
| | - Mira Jun
- Brain Busan 21 Plus Program, Department of Food Science and Nutrition, Graduate School, Center for Silver-Targeted Biomaterials, Dong-A University, Busan, Korea
| | - Woo-Sik Jeong
- Food and Bio-Industry Research Institute, School of Food Science and Biotechnology, College of Agriculture and Life Sciences, Kyungpook National University, Daegu, Korea
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27
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Hernández-Lozano I, Wanek T, Sauberer M, Filip T, Mairinger S, Stanek J, Traxl A, Karch R, Schuetz JD, Langer O. Influence of ABC transporters on the excretion of ciprofloxacin assessed with PET imaging in mice. Eur J Pharm Sci 2021; 163:105854. [PMID: 33865975 DOI: 10.1016/j.ejps.2021.105854] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 12/31/2022]
Abstract
Ciprofloxacin is a commonly prescribed fluoroquinolone antibiotic which is cleared by active tubular secretion and intestinal excretion. Ciprofloxacin is a known substrate of the ATP-binding cassette (ABC) transporters breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 4 (MRP4). In this work, we used positron emission tomography (PET) imaging to investigate the influence of BCRP, MRP4, MRP2 and P-glycoprotein (P-gp) on the excretion of [18F]ciprofloxacin in mice. Dynamic 90-min PET scans were performed after intravenous injection of [18F]ciprofloxacin in wild-type mice without and with pre-treatment with the broad-spectrum MRP inhibitor MK571. Moreover, [18F]ciprofloxacin PET scans were performed in Abcc4(-/-), Abcc2(-/-), Abcc4(-/-)Abcg2(-/-) and Abcb1a/b(-/-)Abcg2(-/-) mice. In addition to non-compartmental pharmacokinetic (PK) analysis, a novel three-compartment PK model was developed for a detailed assessment of the renal disposition of [18F]ciprofloxacin. In MK571 pre-treated mice, a significant increase in the blood exposure to [18F]ciprofloxacin was observed along with a significant reduction in the renal and intestinal clearances. PK modelling revealed a significant reduction in renal radioactivity uptake (CL1) and in the rate constants for transfer of radioactivity from the corticomedullary renal region into blood (k2) and urine (k3), respectively, after MK571 administration. No changes in the renal clearance or in the estimated kidney PK model parameters were observed in any of the studied knockout models, while a significant reduction in the intestinal clearance was observed in Abcc2(-/-) and Abcc4(-/-)Abcg2(-/-) mice. Our data failed to reveal a role of any of the studied ABC transporters in the tubular secretion of ciprofloxacin. This may indicate that ciprofloxacin is handled in the kidneys by more than one transporter family, most likely with a great degree of mutual functional redundancy. Our study highlights the potential of PET imaging for an assessment of transporter-mediated renal excretion of radiolabelled drugs.
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Affiliation(s)
- Irene Hernández-Lozano
- Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
| | - Thomas Wanek
- Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria.
| | - Michael Sauberer
- Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria.
| | - Thomas Filip
- Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria.
| | - Severin Mairinger
- Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria.
| | - Johann Stanek
- Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria.
| | - Alexander Traxl
- Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria.
| | - Rudolf Karch
- Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, 1090 Vienna, Austria.
| | - John D Schuetz
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 38105 Memphis, TN, USA.
| | - Oliver Langer
- Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria; Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, 1090 Vienna, Austria.
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28
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Balla A, Jeong YS, Kim HJ, Lee YJ, Chung SJ, Chae YJ, Maeng HJ. Effects of 1α,25-Dihydroxyvitamin D 3 on the Pharmacokinetics of Procainamide and Its Metabolite N-Acetylprocainamide, Organic Cation Transporter Substrates, in Rats with PBPK Modeling Approach. Pharmaceutics 2021; 13:pharmaceutics13081133. [PMID: 34452094 PMCID: PMC8402143 DOI: 10.3390/pharmaceutics13081133] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/13/2021] [Accepted: 07/22/2021] [Indexed: 11/16/2022] Open
Abstract
In this study, possible changes in the expression of rat organic cationic transporters (rOCTs) and rat multidrug and toxin extrusion proteins (rMATEs) following treatment with 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) were investigated. Rats received intraperitoneal administrations of 1,25(OH)2D3 for four consecutive days, and the tissues of interest were collected. The mRNA expression of rOCT1 in the kidneys was significantly increased in 1,25(OH)2D3-treated rats compared with the control rats, while the mRNA expressions of rOCT2 and rMATE1 in the kidneys, rOCT1 and N-acetyltransferase-II (NAT-II) in the liver, and rOCT3 in the heart were significantly decreased. Changes in the protein expression of hepatic rOCT1 and renal rOCT2 and rMATE1 were confirmed by western blot analysis. We further evaluated the pharmacokinetics of procainamide (PA) hydrochloride and its major metabolite N-acetyl procainamide (NAPA) in the presence of 1,25(OH)2D3. When PA hydrochloride was administered intravenously at a dose 10 mg/kg to 1,25(OH)2D3-treated rats, a significant decrease in renal and/or non-renal clearance of PA and NAPA was observed. A physiological model for the pharmacokinetics of PA and NAPA in rats was useful for linking changes in the transcriptional and translational expressions of rOCTs and rMATE1 transporters to the altered pharmacokinetics of the drugs.
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Affiliation(s)
- Anusha Balla
- College of Pharmacy, Gachon University, Incheon 21936, Korea;
| | - Yoo-Seong Jeong
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea; (Y.-S.J.); (S.-J.C.)
| | - Hyo-Jung Kim
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea; (H.-J.K.); (Y.-J.L.)
| | - Yun-Jong Lee
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea; (H.-J.K.); (Y.-J.L.)
| | - Suk-Jae Chung
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea; (Y.-S.J.); (S.-J.C.)
| | - Yoon-Jee Chae
- College of Pharmacy, Woosuk University, Wanju-gun 55338, Korea
- Correspondence: (Y.-J.C.); (H.-J.M.); Tel.: +82-63-290-1424 (Y.-J.C.); +82-32-820-4935 (H.-J.M.)
| | - Han-Joo Maeng
- College of Pharmacy, Gachon University, Incheon 21936, Korea;
- Correspondence: (Y.-J.C.); (H.-J.M.); Tel.: +82-63-290-1424 (Y.-J.C.); +82-32-820-4935 (H.-J.M.)
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Zhang Y, Sun M, Jian S, Huang J, Xiao C, Zhang X, Hu R, Si L. mPEG 2k-PCL x Polymeric Micelles Influence Pharmacokinetics and Hypoglycemic Efficacy of Metformin through Inhibition of Organic Cation Transporters in Rats. Mol Pharm 2021; 18:2586-2599. [PMID: 34102842 DOI: 10.1021/acs.molpharmaceut.1c00078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Increasing evidence has shown that nanocarriers have effects on several efflux drug transporters. To date, little is known about whether influx transporters are also modulated. Herein, we investigated the impact of amphiphilic polymer micelles on the uptake function of organic cation transporters (OCTs) and the influence on the pharmacokinetics and pharmacodynamics of metformin, a well-characterized substrate of OCTs. Five types of polymeric micelles (mPEG2k-PCL2k, mPEG2k-PCL3.5k, mPEG2k-PCL5k, mPEG2k-PCL7.5k, and mPEG2k-PCL10k) were prepared to evaluate the inhibition of hOCT1-3-overexpressing Madin-Darby canine kidney cells. The mPEG2k-PCLx micelles played an inhibitory role above the critical micelle concentration. The inhibitory potency could be ranked as mPEG2k-PCL2k > mPEG2k-PCL3.5k > mPEG2k-PCL5k > mPEG2k-PCL7.5k > mPEG2k-PCL10k, which negatively declined with the increase of molecular weight of the hydrophobic segment. The inhibitory effects of polymeric micelles on the hOCT1 isoform were the most pronounced, with the lowest IC50 values ranging from 0.106 to 0.280 mg/mL. The mPEG2k-PCL2k micelles distinctly increased the plasma concentration of metformin and significantly decreased Vss by 35.6% (p < 0.05) after seven consecutive treatments in rats, which was interrelated with the restrained metformin distribution in the liver and kidney. The uptake inhibition of micelles on hepatic and renal rOcts also diminished the glucose-lowering effect of metformin and fasting insulin levels in the oral glucose tolerance test. Consistent with the inhibitory effects, the mRNA and protein levels of rOct1 and rOct2 were decreased in the liver, kidney, and small intestine. The present study demonstrated that mPEG2k-PCLx micelles could inhibit the transport function of OCTs, indicating a potential risk of drug-drug interactions during concomitant medication of nanomedicine with organic cationic drugs.
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Affiliation(s)
- Ying Zhang
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, PR China
| | - Minghui Sun
- Department of Pharmaceutics, Affiliated Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, PR China
| | - Shuxin Jian
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, PR China
| | - Jiangeng Huang
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, PR China
| | - Chuyao Xiao
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, PR China
| | - Xiangyu Zhang
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, PR China
| | - Ruhao Hu
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, PR China
| | - Luqin Si
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College of Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, PR China
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30
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Omata Y, Yamauchi T, Tsuruta A, Matsunaga N, Koyanagi S, Ohdo S. RNA editing enzyme ADAR1 governs the circadian expression of P-glycoprotein in human renal cells by regulating alternative splicing of the ABCB1 gene. J Biol Chem 2021; 296:100601. [PMID: 33781748 PMCID: PMC8095175 DOI: 10.1016/j.jbc.2021.100601] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/05/2021] [Accepted: 03/25/2021] [Indexed: 11/04/2022] Open
Abstract
The expression and function of some xenobiotic transporters vary according to the time of the day, causing the dosing time-dependent changes in drug disposition and toxicity. P-glycoprotein (P-gp), encoded by the ABCB1 gene, is highly expressed in the kidneys and functions in the renal elimination of various drugs. The elimination of several P-gp substrates was demonstrated to vary depending on administration time, but the underlying mechanism remains unclear. We found that adenosine deaminase acting on RNA (ADAR1) was involved in the circadian regulation of P-gp expression in human renal proximal tubular epithelial cells (RPTECs). After synchronization of the cellular circadian clock by dexamethasone treatment, the expression of P-gp exhibited a significant 24-h oscillation in RPTECs, but this oscillation was disrupted by the downregulation of ADAR1. Although ADAR1 catalyzes adenosine-to-inosine (A-to-I) RNA editing in double-stranded RNA substrates, no significant ADAR1-regulated editing sites were detected in the human ABCB1 transcripts in RPTECs. On the other hand, downregulation of ADAR1 induced alternative splicing in intron 27 of the human ABCB1 gene, resulting in the production of retained intron transcripts. The aberrant spliced transcript was sensitive to nonsense-mediated mRNA decay, leading to the decreased stability of ABCB1 mRNA and prevention of the 24-h oscillation of P-gp expression. These findings support the notion that ADAR1-mediated regulation of alternative splicing of the ABCB1 gene is a key mechanism of circadian expression of P-gp in RPTECs, and the regulatory mechanism may underlie the dosing time-dependent variations in the renal elimination of P-gp substrates.
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Affiliation(s)
- Yuji Omata
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoaki Yamauchi
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Akito Tsuruta
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoya Matsunaga
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Department of Glocal Healthcare Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Satoru Koyanagi
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Department of Glocal Healthcare Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
| | - Shigehiro Ohdo
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
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31
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Abstract
The study of enzyme kinetics in drug metabolism involves assessment of rates of metabolism and inhibitory potencies over a suitable concentration range. In all but the very simplest in vitro system, these drug concentrations can be influenced by a variety of nonspecific binding reservoirs that can reduce the available concentration to the enzyme system(s) under investigation. As a consequence, the apparent kinetic parameters, such as Km or Ki, that are derived can deviate from the true values. There are a number of sources of these nonspecific binding depots or barriers, including membrane permeation and partitioning, plasma or serum protein binding, and incubational binding. In the latter case, this includes binding to the assay apparatus as well as biological depots, depending on the characteristics of the in vitro matrix being used. Given the wide array of subcellular, cellular, and recombinant enzyme systems utilized in drug metabolism, each of these has different components which can influence the free drug concentration. The physicochemical properties of the test compound are also paramount in determining the influential factors in any deviation between true and apparent kinetic behavior. This chapter describes the underlying mechanisms determining the free drug concentration in vitro and how these factors can be accounted for in drug metabolism studies, illustrated with case studies from the literature.
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Affiliation(s)
- Nigel J Waters
- Preclinical Development, Black Diamond Therapeutics, Cambridge, MA, USA
| | - R Scott Obach
- Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, CT, USA
| | - Li Di
- Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, CT, USA
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Multifaceted Factors Causing Conflicting Outcomes in Herb-Drug Interactions. Pharmaceutics 2020; 13:pharmaceutics13010043. [PMID: 33396770 PMCID: PMC7824553 DOI: 10.3390/pharmaceutics13010043] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 12/27/2020] [Accepted: 12/28/2020] [Indexed: 12/11/2022] Open
Abstract
Metabolic enzyme and/or transporter-mediated pharmacokinetic (PK) changes in a drug caused by concomitant herbal products have been a primary issue of herb and drug interactions (HDIs), because PK changes of a drug may result in the alternation of efficacy and toxicity. Studies on HDIs have been carried out by predictive in vitro and in vivo preclinical studies, and clinical trials. Nevertheless, the discrepancies between predictive data and the clinical significance on HDIs still exist, and different reports of HDIs add to rather than clarify the confusion regarding the use of herbal products and drug combinations. Here, we briefly review the underlying mechanisms causing PK-based HDIs, and more importantly summarize challenging issues, such as dose and treatment period effects, to be considered in study designs and interpretations of HDI evaluations.
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Bechtold B, Clarke J. Multi-factorial pharmacokinetic interactions: unraveling complexities in precision drug therapy. Expert Opin Drug Metab Toxicol 2020; 17:397-412. [PMID: 33339463 DOI: 10.1080/17425255.2021.1867105] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Introduction: Precision drug therapy requires accounting for pertinent factors in pharmacokinetic (PK) inter-individual variability (i.e., pharmacogenetics, diseases, polypharmacy, and natural product use) that can cause sub-therapeutic or adverse effects. Although each of these individual factors can alter victim drug PK, multi-factorial interactions can cause additive, synergistic, or opposing effects. Determining the magnitude and direction of these complex multi-factorial effects requires understanding the rate-limiting redundant and/or sequential PK processes for each drug.Areas covered: Perturbations in drug-metabolizing enzymes and/or transporters are integral to single- and multi-factorial PK interactions. Examples of single factor PK interactions presented include gene-drug (pharmacogenetic), disease-drug, drug-drug, and natural product-drug interactions. Examples of multi-factorial PK interactions presented include drug-gene-drug, natural product-gene-drug, gene-gene-drug, disease-natural product-drug, and disease-gene-drug interactions. Clear interpretation of multi-factorial interactions can be complicated by study design, complexity in victim drug PK, and incomplete mechanistic understanding of victim drug PK.Expert opinion: Incorporation of complex multi-factorial PK interactions into precision drug therapy requires advances in clinical decision tools, intentional PK study designs, drug-metabolizing enzyme and transporter fractional contribution determinations, systems and computational approaches (e.g., physiologically-based pharmacokinetic modeling), and PK phenotyping of progressive diseases.
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Affiliation(s)
- Baron Bechtold
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
| | - John Clarke
- Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
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Keefer C, Chang G, Carlo A, Novak JJ, Banker M, Carey J, Cianfrogna J, Eng H, Jagla C, Johnson N, Jones R, Jordan S, Lazzaro S, Liu J, Scott Obach R, Riccardi K, Tess D, Umland J, Racich J, Varma M, Visswanathan R, Di L. Mechanistic insights on clearance and inhibition discordance between liver microsomes and hepatocytes when clearance in liver microsomes is higher than in hepatocytes. Eur J Pharm Sci 2020; 155:105541. [DOI: 10.1016/j.ejps.2020.105541] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/18/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023]
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Chen L, Choi J, Leonard SW, Banuvar S, Barengolts E, Viana M, Chen SN, Pauli GF, Bolton JL, van Breemen RB. No Clinically Relevant Pharmacokinetic Interactions of a Red Clover Dietary Supplement with Cytochrome P450 Enzymes in Women. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:13929-13939. [PMID: 33197178 PMCID: PMC8071351 DOI: 10.1021/acs.jafc.0c05856] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Extracts of red clover (Trifolium pratense L.), containing estrogenic isoflavones like genistein and daidzein and the proestrogenic isoflavones formononetin and biochanin A, are used by women as dietary supplements for the management of menopausal symptoms. Although marketed as a safer alternative to hormone therapy, red clover isoflavones have been reported to inhibit some cytochrome P450 (CYP) enzymes involved in drug metabolism. To evaluate the potential for clinically relevant drug-red clover interactions, we tested a standardized red clover dietary supplement (120 mg isoflavones per day) for interactions with the pharmacokinetics of four FDA-approved drugs (caffeine, tolbutamide, dextromethorphan, and alprazolam) as probe substrates for the enzymes CYP1A2, CYP2C9, CYP2D6, and CYP3A4/5, respectively. Fifteen peri- and postmenopausal women completed pharmacokinetic studies at baseline and 2 weeks after consuming red clover. The averaged pharmacokinetic profiles of probe substrates in serum showed no significant alterations and no changes in the areas under the curve (AUC) over 96 h. Subgroup analysis based on the demographic characteristics (BMI, menopausal status, race, and age) also showed no differences in AUC for each probe substrate. Analysis of red clover isoflavones in serum showed primarily conjugated metabolites that explain, at least in part, the red clover pharmacokinetic safety profile.
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Affiliation(s)
- Luying Chen
- Linus Pauling Institute, Oregon State University, 2900 SW Campus Way, Corvallis, OR, 97331
- College of Pharmacy, Oregon State University, 1601 SW Jefferson Way, Corvallis, OR, 97331
- UIC/NIH Center for Botanical Dietary Supplements Research, Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, 833 S. Wood St., Chicago, IL 60612
| | - Jaewoo Choi
- Linus Pauling Institute, Oregon State University, 2900 SW Campus Way, Corvallis, OR, 97331
| | - Scott W. Leonard
- Linus Pauling Institute, Oregon State University, 2900 SW Campus Way, Corvallis, OR, 97331
| | - Suzanne Banuvar
- UIC/NIH Center for Botanical Dietary Supplements Research, Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, 833 S. Wood St., Chicago, IL 60612
| | - Elena Barengolts
- UIC/NIH Center for Botanical Dietary Supplements Research, Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, 833 S. Wood St., Chicago, IL 60612
| | - Marlos Viana
- UIC/NIH Center for Botanical Dietary Supplements Research, Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, 833 S. Wood St., Chicago, IL 60612
| | - Shao-Nong Chen
- UIC/NIH Center for Botanical Dietary Supplements Research, Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, 833 S. Wood St., Chicago, IL 60612
| | - Guido F. Pauli
- UIC/NIH Center for Botanical Dietary Supplements Research, Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, 833 S. Wood St., Chicago, IL 60612
| | - Judy L. Bolton
- UIC/NIH Center for Botanical Dietary Supplements Research, Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, 833 S. Wood St., Chicago, IL 60612
| | - Richard B. van Breemen
- Linus Pauling Institute, Oregon State University, 2900 SW Campus Way, Corvallis, OR, 97331
- College of Pharmacy, Oregon State University, 1601 SW Jefferson Way, Corvallis, OR, 97331
- UIC/NIH Center for Botanical Dietary Supplements Research, Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, 833 S. Wood St., Chicago, IL 60612
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Li N, Badrinarayanan A, Ishida K, Li X, Roberts J, Wang S, Hayashi M, Gupta A. Albumin-Mediated Uptake Improves Human Clearance Prediction for Hepatic Uptake Transporter Substrates Aiding a Mechanistic In Vitro-In Vivo Extrapolation (IVIVE) Strategy in Discovery Research. AAPS JOURNAL 2020; 23:1. [DOI: 10.1208/s12248-020-00528-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/16/2020] [Indexed: 01/09/2023]
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Tess DA, Eng H, Kalgutkar AS, Litchfield J, Edmonds DJ, Griffith DA, Varma MVS. Predicting the Human Hepatic Clearance of Acidic and Zwitterionic Drugs. J Med Chem 2020; 63:11831-11844. [PMID: 32985885 DOI: 10.1021/acs.jmedchem.0c01033] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Prospective predictions of human hepatic clearance for anionic/zwitterionic compounds, which are oftentimes subjected to transporter-mediated uptake, are challenging in drug discovery. We evaluated the utility of preclinical species, rats and cynomolgus monkeys [nonhuman primates (NHPs)], to predict the human hepatic clearance using a diverse set of acidic/zwitterionic drugs. Preclinical clearance data were generated following intravenous dosing in rats/NHPs and compared to the human clearance data (n = 18/27). Single-species scaling of NHP clearance with an allometric exponent of 0.50 allowed for good prediction of human clearance (fold error ∼2.1, bias ∼1.0), with ∼86% predictions within 3-fold. In comparison, rats underpredicted the clearance of lipophilic acids, while overprediction was noted for hydrophilic acids. Finally, an in vitro clearance assay based on human hepatocytes, which is routinely used in discovery setting, markedly underpredicted human clearance (bias ∼0.12). Collectively, this study provides insights into the usefulness of the preclinical models in enabling pharmacokinetic optimization for acid/zwitterionic drug candidates.
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Affiliation(s)
- David A Tess
- Medicine Design, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
| | - Heather Eng
- Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
| | - Amit S Kalgutkar
- Medicine Design, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
| | - John Litchfield
- Medicine Design, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
| | - David J Edmonds
- Medicine Design, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
| | - David A Griffith
- Medicine Design, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
| | - Manthena V S Varma
- Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
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38
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Li N, Badrinarayanan A, Li X, Roberts J, Hayashi M, Virk M, Gupta A. Comparison of In Vitro to In Vivo Extrapolation Approaches for Predicting Transporter-Mediated Hepatic Uptake Clearance Using Suspended Rat Hepatocytes. Drug Metab Dispos 2020; 48:861-872. [PMID: 32759366 DOI: 10.1124/dmd.120.000064] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 07/08/2020] [Indexed: 12/15/2022] Open
Abstract
Clearance (CL) prediction remains a significant challenge in drug discovery, especially when complex processes such as drug transporters are involved. The present work explores various in vitro to in vivo extrapolation (IVIVE) approaches to predict hepatic CL driven by uptake transporters in rat. Broadly, two different IVIVE methods using suspended rat hepatocytes were compared: initial uptake CL (PSu,inf) and intrinsic metabolic CL (CLint,met) corrected by unbound hepatocytes to medium partition coefficient (Kpuu). Kpuu was determined by temperature method (Temp Kpuu,ss), homogenization method (Hom Kpuu,ss), and initial rate method (Kpuu,V0). In addition, the impact of bovine serum albumin (BSA) on each of these methods was investigated. Twelve compounds, which are known substrates of organic anion-transporting polypeptides representing diverse chemical matter, were selected for these studies. As expected, CLint,met alone significantly underestimated hepatic CL for all the test compounds. Overall, predicted hepatic CL using PSu,inf with BSA, Hom Kpuu,ss with BSA, and Temp Kpuu,ss showed the most robust correlation with in vivo rat hepatic CL. Adding BSA improved hepatic CL prediction for selected compounds when using the PSu,inf and Hom Kpuu,ss methods, with minimal impact on the Temp Kpuu,ss and Kpuu,V0 methods. None of the IVIVE approaches required an empirical scaling factor. These results suggest that supplementing rat hepatocyte suspension with BSA may be essential in drug discovery research for novel chemical matters to improve CL prediction. SIGNIFICANCE STATEMENT: The current investigation demonstrates that hepatocyte uptake assay supplemented with 4% bovine serum albumin is a valuable tool for estimating unbound hepatic uptake clearance (CL) and Kpuu. Based upon the extended clearance concept, direct extrapolation from these in vitro parameters significantly improved the overall hepatic CL prediction for organic anion-transporting polypeptide substrates in rat. This study provides a practical in vitro to in vivo extrapolation strategy for predicting transporter-mediated hepatic CL in early drug discovery.
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Affiliation(s)
- Na Li
- Department of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., Cambridge, Massachusetts
| | - Akshay Badrinarayanan
- Department of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., Cambridge, Massachusetts
| | - Xingwen Li
- Department of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., Cambridge, Massachusetts
| | - John Roberts
- Department of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., Cambridge, Massachusetts
| | - Mike Hayashi
- Department of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., Cambridge, Massachusetts
| | - Manpreet Virk
- Department of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., Cambridge, Massachusetts
| | - Anshul Gupta
- Department of Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., Cambridge, Massachusetts
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Di L, Artursson P, Avdeef A, Benet LZ, Houston JB, Kansy M, Kerns EH, Lennernäs H, Smith DA, Sugano K. The Critical Role of Passive Permeability in Designing Successful Drugs. ChemMedChem 2020; 15:1862-1874. [PMID: 32743945 DOI: 10.1002/cmdc.202000419] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Indexed: 12/25/2022]
Abstract
Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.
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Affiliation(s)
- Li Di
- Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, 445 Eastern Point Road, Groton, CT 06340, USA
| | - Per Artursson
- Department of Pharmacy, Uppsala University, 752 36, Uppsala, Sweden
| | - Alex Avdeef
- in-ADME Research, 1732 First Avenue, #102, New York, NY 10128, USA
| | - Leslie Z Benet
- Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA 94143, USA
| | - J Brian Houston
- Division of Pharmacy & Optometry, Stopford Building, Oxford Road, Manchester, M13 9PT, UK
| | | | | | - Hans Lennernäs
- Department of Pharmacy, Uppsala University, 752 36, Uppsala, Sweden
| | | | - Kiyohiko Sugano
- College of Pharmaceutical Sciences, Department of Pharmacy, Ritsumeikan University, Noji-higashi, Kusatsu, Shiga, 525-8577, Japan
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40
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Saravanakumar A, Sadighi A, Ryu R, Akhlaghi F. Physicochemical Properties, Biotransformation, and Transport Pathways of Established and Newly Approved Medications: A Systematic Review of the Top 200 Most Prescribed Drugs vs. the FDA-Approved Drugs Between 2005 and 2016. Clin Pharmacokinet 2020; 58:1281-1294. [PMID: 30972694 DOI: 10.1007/s40262-019-00750-8] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism and physicochemical properties of the top 200 most prescribed drugs (established) as well as drugs approved by the US Food and Drug Administration (FDA) between 2005 and 2016 (newly approved). OBJECTIVE Our objective was to capture the changing trends in the routes of administration, physicochemical properties, and prodrug medications, as well as the contributions of drug-metabolizing enzymes and transporters to drug clearance. METHODS The University of Washington Drug Interaction Database (DIDB®) as well as other online resources (e.g., CenterWatch.com, Drugs.com, DrugBank.ca, and PubChem.ncbi.nlm.nih.gov) was used to collect and stratify the dataset required for exploring the above-mentioned trends. RESULTS Analyses revealed that ~ 90% of all drugs in the established and newly approved drug lists were administered systemically (oral or intravenous). Meanwhile, the portion of biologics (molecular weight > 1 kDa) was 15 times greater in the newly approved list than established drugs. Additionally, there was a 4.5-fold increase in the number of compounds with a high calculated partition coefficient (cLogP > 3) and a high total polar surface area (> 75 Å2) in the newly approved drug vs. the established category. Further, prodrugs in established or newly approved lists were found to be converted to active compounds via hydrolysis, demethylases, and kinases. The contribution of cytochrome P450 (CYP) 3A4, as the major biotransformation pathway, has increased from 40% in the established drug list to 64% in the newly approved drug list. Moreover, the role of CYP1A2, CYP2C19, and CYP2D6 were decreased as major metabolizing enzymes among the newly approved medications. Among non-CYP major metabolizers, the contribution of alcohol dehydrogenases/aldehyde dehydrogenases (ADH/ALDH) and sulfotransferases decreased in the newly approved drugs compared with the established list. Furthermore, the highest contribution among uptake and efflux transporters was found for Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp), respectively. CONCLUSIONS The higher portion of biologics in the newly approved drugs compared with the established list confirmed the growing demands for protein- and antibody-based therapies. Moreover, the larger number of hydrophilic drugs found in the newly approved list suggests that the probability of toxicity is likely to decrease. With regard to CYP-mediated major metabolism, CYP3A5 showed an increased involvement owing to the identification of unique probe substrates to differentiate CYP3As. Furthermore, the contribution of OATP1B1 and P-gp did not show a significant shift in the newly approved drugs as compared to the established list because of their broad substrate specificity.
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Affiliation(s)
- Anitha Saravanakumar
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Office 495 A, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Armin Sadighi
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Office 495 A, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Rachel Ryu
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Office 495 A, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Fatemeh Akhlaghi
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Office 495 A, 7 Greenhouse Road, Kingston, RI, 02881, USA.
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Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity. Sci Rep 2020; 10:13484. [PMID: 32778717 PMCID: PMC7417537 DOI: 10.1038/s41598-020-70321-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 06/11/2020] [Indexed: 12/29/2022] Open
Abstract
The expression and function of some xenobiotic transporters varies according to the time of day, causing the dosing time-dependent changes in drug disposition and toxicity. Multidrug resistance-associated protein-4 (MRP4), an ATPbinding cassette (ABC) efflux transporter encoded by the Abcc4 gene, is highly expressed in bone marrow cells (BMCs) and protects them against xenobiotics, including chemotherapeutic drugs. In this study, we demonstrated that MRP4 was responsible for the extrusion of oxaliplatin (L-OHP), a platinum (Pt)-based chemotherapeutic drug, from BMCs of mice, and that the efflux transporter expression exhibited significant diurnal variation. Therefore, we investigated the relevance of the diurnal expression of MRP4 in BMCs for L-OHP-induced myelotoxicity in mice maintained under standardized light/dark cycle conditions. After intravenous injection of L-OHP, the Pt content in BMCs varied according to the injection time. Lower Pt accumulation in BMCs was detected in mice after injection of L-OHP at the mid-dark phase, during which the expression levels of MRP4 increased. Consistent with these observations, the myelotoxic effects of L-OHP were attenuated when mice were injected with L-OHP during the dark phase. This dosing schedule also alleviated the L-OHP-induced reduction of the peripheral white blood cell count. The present results suggest that the myelotoxicity of L-OHP is attenuated by optimizing the dosing schedule. Diurnal expression of MRP4 in BMCs is associated with the dosing time-dependent changes in L-OHP-induced myelotoxicity.
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Sanoh S, Naritomi Y, Kitamura S, Shinagawa A, Kakuni M, Tateno C, Ohta S. Predictability of human pharmacokinetics of drugs that undergo hepatic organic anion transporting polypeptide (OATP)-mediated transport using single-species allometric scaling in chimeric mice with humanized liver: integration with hepatic drug metabolism. Xenobiotica 2020; 50:1370-1379. [PMID: 32401667 DOI: 10.1080/00498254.2020.1769229] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
We previously reported a prediction method for human pharmacokinetics (PK) using single species allometric scaling (SSS) and the complex Dedrick plot in chimeric mice with humanized liver to predict the total clearance (CLt), distribution volumes in steady state (Vdss) and plasma concentration-time profiles of several drugs metabolized by cytochrome P450 (P450) and non-P450 enzymes. In the present study, we examined eight compounds (bosentan, cerivastatin, fluvastatin, pitavastatin, pravastatin, repaglinide, rosuvastatin, valsartan) as typical organic anion transporting polypeptide (OATP) substrates and six compounds metabolized by P450 and non-P450 enzymes to evaluate the predictability of CLt, Vdss and plasma concentration-time profiles after intravenous administration to chimeric mice. The predicted CLt and Vdss of drugs that undergo OATP-mediated uptake and P450/non-P450-mediated metabolism reflected the observed data from humans within a threefold error range. We also examined the possibility of predicting plasma concentration-time profiles of drugs that undergo OATP-mediated uptake using the complex Dedrick plot in chimeric mice. Most profiles could be superimposed with observed profiles from humans within a two- to threefold error range. PK prediction using SSS and the complex Dedrick plot in chimeric mice can be useful for evaluating drugs that undergo both OATP-mediated uptake and P450/non-P450-mediated metabolism.
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Affiliation(s)
- Seigo Sanoh
- Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,School of Pharmaceutical Sciences, Hiroshima University, Hiroshima, Japan
| | - Yoichi Naritomi
- Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc, Tsukuba, Japan
| | - Satoshi Kitamura
- Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc, Tsukuba, Japan
| | - Akihiko Shinagawa
- School of Pharmaceutical Sciences, Hiroshima University, Hiroshima, Japan
| | | | - Chise Tateno
- R&D Dept, PhoenixBio, Co., Ltd, Higashi-Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Higashi-Hiroshima, Japan
| | - Shigeru Ohta
- Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,School of Pharmaceutical Sciences, Hiroshima University, Hiroshima, Japan.,Wakayama Medical University, Wakayama, Japan
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Interpretation of Drug Interaction Using Systemic and Local Tissue Exposure Changes. Pharmaceutics 2020; 12:pharmaceutics12050417. [PMID: 32370191 PMCID: PMC7284846 DOI: 10.3390/pharmaceutics12050417] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 12/13/2022] Open
Abstract
Systemic exposure of a drug is generally associated with its pharmacodynamic (PD) effect (e.g., efficacy and toxicity). In this regard, the change in area under the plasma concentration-time curve (AUC) of a drug, representing its systemic exposure, has been mainly considered in evaluation of drug-drug interactions (DDIs). Besides the systemic exposure, the drug concentration in the tissues has emerged as a factor to alter the PD effects. In this review, the status of systemic exposure, and/or tissue exposure changes in DDIs, were discussed based on the recent reports dealing with transporters and/or metabolic enzymes mediating DDIs. Particularly, the tissue concentration in the intestine, liver and kidney were referred to as important factors of PK-based DDIs.
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Kimoto E, Obach RS, Varma MV. Identification and quantitation of enzyme and transporter contributions to hepatic clearance for the assessment of potential drug-drug interactions. Drug Metab Pharmacokinet 2020; 35:18-29. [DOI: 10.1016/j.dmpk.2019.11.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/30/2019] [Accepted: 11/13/2019] [Indexed: 12/18/2022]
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45
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Nozaki Y, Izumi S. Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters. Drug Metab Pharmacokinet 2020; 35:56-70. [DOI: 10.1016/j.dmpk.2019.11.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 09/29/2019] [Accepted: 11/02/2019] [Indexed: 12/26/2022]
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Hernández Lozano I, Langer O. Use of imaging to assess the activity of hepatic transporters. Expert Opin Drug Metab Toxicol 2020; 16:149-164. [PMID: 31951754 PMCID: PMC7055509 DOI: 10.1080/17425255.2020.1718107] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/15/2020] [Indexed: 12/13/2022]
Abstract
Introduction: Membrane transporters of the SLC and ABC families are abundantly expressed in the liver, where they control the transfer of drugs/drug metabolites across the sinusoidal and canalicular hepatocyte membranes and play a pivotal role in hepatic drug clearance. Noninvasive imaging methods, such as PET, SPECT or MRI, allow for measuring the activity of hepatic transporters in vivo, provided that suitable transporter imaging probes are available.Areas covered: We give an overview of the working principles of imaging-based assessment of hepatic transporter activity. We discuss different currently available PET/SPECT radiotracers and MRI contrast agents and their applications to measure hepatic transporter activity in health and disease. We cover mathematical modeling approaches to obtain quantitative parameters of transporter activity and provide a critical assessment of methodological limitations and challenges associated with this approach.Expert opinion: PET in combination with pharmacokinetic modeling can be potentially applied in drug development to study the distribution of new drug candidates to the liver and their clearance mechanisms. This approach bears potential to mechanistically assess transporter-mediated drug-drug interactions, to assess the influence of disease on hepatic drug disposition and to validate and refine currently available in vitro-in vivo extrapolation methods to predict hepatic clearance of drugs.
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Affiliation(s)
| | - Oliver Langer
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
- Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
- Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
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Orozco CC, Atkinson K, Ryu S, Chang G, Keefer C, Lin J, Riccardi K, Mongillo RK, Tess D, Filipski KJ, Kalgutkar AS, Litchfield J, Scott D, Di L. Structural attributes influencing unbound tissue distribution. Eur J Med Chem 2020; 185:111813. [DOI: 10.1016/j.ejmech.2019.111813] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 09/03/2019] [Accepted: 10/23/2019] [Indexed: 12/26/2022]
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Baidya ATK, Ghosh K, Amin SA, Adhikari N, Nirmal J, Jha T, Gayen S. In silico modelling, identification of crucial molecular fingerprints, and prediction of new possible substrates of human organic cationic transporters 1 and 2. NEW J CHEM 2020. [DOI: 10.1039/c9nj05825g] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The cation membrane transporters are crucial to regulate movement of foreign molecules within the body. The present study found out structural fingerprints within molecules to be recognized as substrate/non-substrate against these transporters.
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Affiliation(s)
- Anurag T. K. Baidya
- Laboratory of Drug Design and Discovery
- Department of Pharmaceutical Sciences
- Dr H. S. Gour University
- Sagar
- India
| | - Kalyan Ghosh
- Laboratory of Drug Design and Discovery
- Department of Pharmaceutical Sciences
- Dr H. S. Gour University
- Sagar
- India
| | - Sk. Abdul Amin
- Natural Science Laboratory
- Division of Medicinal and Pharmaceutical Chemistry
- Department of Pharmaceutical Technology
- Jadavpur University
- Kolkata
| | - Nilanjan Adhikari
- Natural Science Laboratory
- Division of Medicinal and Pharmaceutical Chemistry
- Department of Pharmaceutical Technology
- Jadavpur University
- Kolkata
| | - Jayabalan Nirmal
- Translational Pharmaceutics Laboratory
- Department of Pharmacy
- BITS-Pilani
- Hyderabad Campus
- Hyderabad 500078
| | - Tarun Jha
- Natural Science Laboratory
- Division of Medicinal and Pharmaceutical Chemistry
- Department of Pharmaceutical Technology
- Jadavpur University
- Kolkata
| | - Shovanlal Gayen
- Laboratory of Drug Design and Discovery
- Department of Pharmaceutical Sciences
- Dr H. S. Gour University
- Sagar
- India
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Callegari E, Varma MVS, Obach RS. Prediction of Metabolite-to-Parent Drug Exposure: Derivation and Application of a Mechanistic Static Model. Clin Transl Sci 2019; 13:520-528. [PMID: 31880865 PMCID: PMC7214656 DOI: 10.1111/cts.12734] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 11/27/2019] [Indexed: 12/02/2022] Open
Abstract
In the development of new drugs, the prediction of metabolite‐to‐parent plasma exposure ratio in humans prior to administration in a clinical study has emerged as an important need. In this work, we derived a mechanistic static model based on first principles to estimate metabolite‐to‐parent plasma exposure ratio, considering the contribution of liver and gut metabolism and drug transport. Knowledge (or assumptions) of mechanisms of clearance and organs involved is required. Input parameters needed included intrinsic clearance, fraction of clearance to the metabolite of interest, various binding values, and, in some cases, active transport clearance. The principles are illustrated with four drugs that yield six metabolites, with one in which clearance is dependent on a pathway subject to genetic polymorphism. Overall, the approach yielded metabolite‐to‐parent ratios within about twofold of the actual values and, thus, can be valuable in decision making in the drug development process.
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Affiliation(s)
- Ernesto Callegari
- Pharmacokinetics, Pharmacodynamics, & Metabolism, Medicine Design, Pfizer Inc., Groton, Connecticut, USA
| | - Manthena V S Varma
- Pharmacokinetics, Pharmacodynamics, & Metabolism, Medicine Design, Pfizer Inc., Groton, Connecticut, USA
| | - R Scott Obach
- Pharmacokinetics, Pharmacodynamics, & Metabolism, Medicine Design, Pfizer Inc., Groton, Connecticut, USA
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Hernández Lozano I, Bauer M, Wulkersdorfer B, Traxl A, Philippe C, Weber M, Häusler S, Stieger B, Jäger W, Mairinger S, Wanek T, Hacker M, Zeitlinger M, Langer O. Measurement of Hepatic ABCB1 and ABCG2 Transport Activity with [ 11C]Tariquidar and PET in Humans and Mice. Mol Pharm 2019; 17:316-326. [PMID: 31790256 DOI: 10.1021/acs.molpharmaceut.9b01060] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) in the canalicular membrane of hepatocytes mediate the biliary excretion of drugs and drug metabolites. To measure hepatic ABCB1 and ABCG2 activity, we performed positron emission tomography (PET) scans with the ABCB1/ABCG2 substrate [11C]tariquidar in healthy volunteers and wild-type, Abcb1a/b(-/-), Abcg2(-/-), and Abcb1a/b(-/-)Abcg2(-/-) mice without and with coadministration of unlabeled tariquidar. PET data were analyzed with a three-compartment pharmacokinetic model. [11C]Tariquidar underwent hepatobiliary excretion in both humans and mice, and tariquidar coadministration caused a significant reduction in the rate constant for the transfer of radioactivity from the liver into bile (by -74% in humans and by -62% in wild-type mice), suggesting inhibition of canalicular efflux transporter activity. Radio-thin-layer chromatography analysis revealed that the majority of radioactivity (>87%) in the mouse liver and bile was composed of unmetabolized [11C]tariquidar. PET data in transporter knockout mice revealed that both ABCB1 and ABCG2 mediated biliary excretion of [11C]tariquidar. In vitro experiments indicated that tariquidar is not a substrate of major hepatic basolateral uptake transporters (SLCO1B1, SLCO1B3, SLCO2B1, SLC22A1, and SLC22A3). Our data suggest that [11C]tariquidar can be used to measure hepatic canalicular ABCB1/ABCG2 transport activity without a confounding effect of uptake transporters.
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Affiliation(s)
- Irene Hernández Lozano
- Department of Clinical Pharmacology , Medical University of Vienna , Vienna 1090 , Austria
| | - Martin Bauer
- Department of Clinical Pharmacology , Medical University of Vienna , Vienna 1090 , Austria
| | - Beatrix Wulkersdorfer
- Department of Clinical Pharmacology , Medical University of Vienna , Vienna 1090 , Austria
| | - Alexander Traxl
- Preclinical Molecular Imaging , AIT Austrian Institute of Technology GmbH , Seibersdorf 2444 , Austria
| | - Cécile Philippe
- Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy , Medical University of Vienna , Vienna 1090 , Austria
| | - Maria Weber
- Department of Clinical Pharmacology , Medical University of Vienna , Vienna 1090 , Austria
| | - Stephanie Häusler
- Department of Clinical Pharmacology and Toxicology , University Hospital Zurich, University of Zurich , Zurich 8006 , Switzerland
| | - Bruno Stieger
- Department of Clinical Pharmacology and Toxicology , University Hospital Zurich, University of Zurich , Zurich 8006 , Switzerland
| | - Walter Jäger
- Department of Clinical Pharmacy and Diagnostics , University of Vienna , Vienna 1090 , Austria
| | - Severin Mairinger
- Preclinical Molecular Imaging , AIT Austrian Institute of Technology GmbH , Seibersdorf 2444 , Austria
| | - Thomas Wanek
- Preclinical Molecular Imaging , AIT Austrian Institute of Technology GmbH , Seibersdorf 2444 , Austria
| | - Marcus Hacker
- Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy , Medical University of Vienna , Vienna 1090 , Austria
| | - Markus Zeitlinger
- Department of Clinical Pharmacology , Medical University of Vienna , Vienna 1090 , Austria
| | - Oliver Langer
- Department of Clinical Pharmacology , Medical University of Vienna , Vienna 1090 , Austria.,Preclinical Molecular Imaging , AIT Austrian Institute of Technology GmbH , Seibersdorf 2444 , Austria.,Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy , Medical University of Vienna , Vienna 1090 , Austria
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