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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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Cai H, Du X, Deng Y, Cao D, Wang L, Wu Z, Zhang X, Xu J, Xie B. Pharmacokinetics and apparent Michaelis constant for metabolite conversion of sorafenib in healthy and hepatocellular carcinoma-bearing rats. Bioanalysis 2024; 16:461-473. [PMID: 38530220 PMCID: PMC11216244 DOI: 10.4155/bio-2023-0215] [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: 10/18/2023] [Accepted: 02/29/2024] [Indexed: 03/27/2024] Open
Abstract
Aim: Investigation of the pharmacokinetics of sorafenib (SRF) in rats with hepatocellular carcinoma (HCC). Methods: A reproducible ultra-HPLC-MS method for simultaneous determination of serum SRF, N-hydroxymethyl sorafenib and N-demethylation sorafenib. Results: Both the maximum serum concentrations (2.5-times) and the area under the serum concentration-time curve from 0 h to infinity (4.5-times) of SRF were observed to be significantly higher, with a greater than 3.0-fold decrease in the clearance rate in the HCC-bearing rats compared with these values in healthy animals. Further study revealed approximately 3.8- and 3.2-times increases in the apparent Michaelis constant for N-hydroxymethyl sorafenib and N-demethylation sorafenib conversions in the HCC-bearing rats. Conclusion: The low efficiency for the SRF conversions was a key contributor to the increased serum concentrations of SRF.
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Affiliation(s)
- Hongxin Cai
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310000, China
- Medical College of Jiaxing University, Key Laboratory of Medical Electronics & Digital Health of Zhejiang Province, Jiaxing University, Jiaxing, 314001, China
| | - Xiaoyue Du
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310000, China
- Medical College of Jiaxing University, Key Laboratory of Medical Electronics & Digital Health of Zhejiang Province, Jiaxing University, Jiaxing, 314001, China
| | - Yufeng Deng
- School of Pharmaceutical Science, Nanchang University, Nanchang, 330001, China
| | - Dejian Cao
- Medical College of Jiaxing University, Key Laboratory of Medical Electronics & Digital Health of Zhejiang Province, Jiaxing University, Jiaxing, 314001, China
| | - Lele Wang
- Medical College of Jiaxing University, Key Laboratory of Medical Electronics & Digital Health of Zhejiang Province, Jiaxing University, Jiaxing, 314001, China
| | - Zhiguo Wu
- School of Pharmaceutical Science, Nanchang University, Nanchang, 330001, China
| | - Xianchao Zhang
- Medical College of Jiaxing University, Key Laboratory of Medical Electronics & Digital Health of Zhejiang Province, Jiaxing University, Jiaxing, 314001, China
| | - Jinbiao Xu
- Medical College of Jiaxing University, Key Laboratory of Medical Electronics & Digital Health of Zhejiang Province, Jiaxing University, Jiaxing, 314001, China
| | - Baogang Xie
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310000, China
- Medical College of Jiaxing University, Key Laboratory of Medical Electronics & Digital Health of Zhejiang Province, Jiaxing University, Jiaxing, 314001, China
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Adiwidjaja J, Spires J, Brouwer KLR. Physiologically Based Pharmacokinetic (PBPK) Model Predictions of Disease Mediated Changes in Drug Disposition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD). Pharm Res 2024; 41:441-462. [PMID: 38351228 DOI: 10.1007/s11095-024-03664-8] [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: 12/07/2023] [Accepted: 01/18/2024] [Indexed: 03/13/2024]
Abstract
PURPOSE This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling approach for prediction of disease-related changes in drug pharmacokinetics. METHODS A virtual NAFLD patient population was developed in GastroPlus (v.9.8.2) by accounting for pathophysiological changes associated with the disease and proteomics-informed alterations in the abundance of metabolizing enzymes and transporters pertinent to drug disposition. The NAFLD population model was verified using exemplar drugs where elimination is influenced predominantly by cytochrome P450 (CYP) enzymes (chlorzoxazone, caffeine, midazolam, pioglitazone) or by transporters (rosuvastatin, 11C-metformin, morphine and the glucuronide metabolite of morphine). RESULTS PBPK model predictions of plasma concentrations of all the selected drugs and hepatic radioactivity levels of 11C-metformin were consistent with the clinically-observed data. Importantly, the PBPK simulations using the virtual NAFLD population model provided reliable estimates of the extent of changes in key pharmacokinetic parameters for the exemplar drugs, with mean predicted ratios (NAFLD patients divided by healthy individuals) within 0.80- to 1.25-fold of the clinically-reported values, except for midazolam (prediction-fold difference of 0.72). CONCLUSION A virtual NAFLD population model within the PBPK framework was successfully developed with good predictive capability of estimating disease-related changes in drug pharmacokinetics. This supports the use of a PBPK modeling approach for prediction of the pharmacokinetics of new investigational or repurposed drugs in patients with NAFLD and may help inform dose adjustments for drugs commonly used to treat comorbidities in this patient population.
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Affiliation(s)
- Jeffry Adiwidjaja
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Simulations Plus, Inc, Lancaster, CA, USA
| | | | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Murphy WA, Adiwidjaja J, Sjöstedt N, Yang K, Beaudoin JJ, Spires J, Siler SQ, Neuhoff S, Brouwer KLR. Considerations for Physiologically Based Modeling in Liver Disease: From Nonalcoholic Fatty Liver (NAFL) to Nonalcoholic Steatohepatitis (NASH). Clin Pharmacol Ther 2023; 113:275-297. [PMID: 35429164 PMCID: PMC10083989 DOI: 10.1002/cpt.2614] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 04/05/2022] [Indexed: 01/27/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), representing a clinical spectrum ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), is rapidly evolving into a global pandemic. Patients with NAFLD are burdened with high rates of metabolic syndrome-related comorbidities resulting in polypharmacy. Therefore, it is crucial to gain a better understanding of NAFLD-mediated changes in drug disposition and efficacy/toxicity. Despite extensive clinical pharmacokinetic data in cirrhosis, current knowledge concerning pharmacokinetic alterations in NAFLD, particularly at different stages of disease progression, is relatively limited. In vitro-to-in vivo extrapolation coupled with physiologically based pharmacokinetic and pharmacodynamic (IVIVE-PBPK/PD) modeling offers a promising approach for optimizing pharmacologic predictions while refining and reducing clinical studies in this population. Use of IVIVE-PBPK to predict intra-organ drug concentrations at pharmacologically relevant sites of action is particularly advantageous when it can be linked to pharmacodynamic effects. Quantitative systems pharmacology/toxicology (QSP/QST) modeling can be used to translate pharmacokinetic and pharmacodynamic data from PBPK/PD models into clinically relevant predictions of drug response and toxicity. In this review, a detailed summary of NAFLD-mediated alterations in human physiology relevant to drug absorption, distribution, metabolism, and excretion (ADME) is provided. The application of literature-derived physiologic parameters and ADME-associated protein abundance data to inform virtual NAFLD population development and facilitate PBPK/PD, QSP, and QST predictions is discussed along with current limitations of these methodologies and knowledge gaps. The proposed methodologic framework offers great potential for meaningful prediction of pharmacological outcomes in patients with NAFLD and can inform both drug development and clinical practice for this population.
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Affiliation(s)
- William A Murphy
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jeffry Adiwidjaja
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Simulations Plus, Inc., Lancaster, California, USA
| | - Noora Sjöstedt
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Kyunghee Yang
- DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | - James J Beaudoin
- DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | | | - Scott Q Siler
- DILIsym Services Division, Simulations Plus Inc., Research Triangle Park, North Carolina, USA
| | | | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Salama S, Kue CS, Mohamad H, Omer F, Ibrahim MY, Abdulla M, Ali H, Mariod A, Jayash SN. Hepatoprotective potential of a novel quinazoline derivative in thioacetamide-induced liver toxicity. Front Pharmacol 2022; 13:943340. [PMID: 36204229 PMCID: PMC9531777 DOI: 10.3389/fphar.2022.943340] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
Purpose: The compound quinazoline Q-Br, 3-(5-bromo-2-hydroxybenzylideneamino)-2-(5-bromo-2 hydroxyphenyl) 2,3-dihydroquinazoline-4(1H)-one (Q-Br) was evaluated for its antioxidant capacity and potential hepatoprotectivity against sub-chronic liver toxicity induced by thioacetamide in rats. Materials and Methods: Rats were assigned into five groups; healthy (normal) and cirrhosis control groups were given 5% Tween 20 orally, the reference control group was given a Silymarin dose of 50 mg/kg, and low-dose Q-Br and high-dose Q-Br groups were given a daily dose of 25 mg/kg and 50 mg/g Q-Br, respectively. Liver status was detected via fluorescence imaging with intravenous injection of indocyanine green (ICG) and a plasma ICG clearance test. Liver malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were also tested. The degree of fibrosis was determined histologically by hematoxylin and eosin and Masson's Trichrome staining. The immunohistochemistry of liver tissue inhibitor of metalloproteinase (TIMP-1), matrix metalloproteinase (MMP-2), and alpha-smooth muscle actin (α-SMA) was performed. Results: Q-Br recorded mild antioxidant capacity, dose-dependent improvement in the liver status, and inhibition of oxidative stress compared to cirrhosis control. Histopathology notified a remarkable reduction in the degree of fibrosis. Immunohistochemistry revealed an obvious low expression of MMP-2 and α-SMA along with a higher expression of TIMP-1 in Q-Br- and Silymarin-treated livers. Conclusion: Q-Br treatment altered the course of toxicity induced by thioacetamide suggesting significant hepatoprotective potential of Q-Br treatment.
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Affiliation(s)
- Suzy Salama
- Indigenous Knowledge and Heritage Center, Ghibaish College of Science and Technology, Ghibaish, Sudan
| | - Chin Siang Kue
- Faculty of Health and Life Sciences, Management and Science University, Shah Alam, Selangor, Malaysia
| | - Haryanti Mohamad
- Animal Experimental Unit, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Fatima Omer
- Department of Chemistry and Biology, Faculty of Education-Hantoub, University of Gezira, Gezira, Sudan
| | | | | | - Hapipah Ali
- Department of General Biology, College of Science, Cihan University-Erbil, Erbil, Kurdistan, Iraq
| | - Abdalbasit Mariod
- Indigenous Knowledge and Heritage Center, Ghibaish College of Science and Technology, Ghibaish, Sudan
- Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
| | - Soher Nagi Jayash
- Faculty of Science & Arts, University of Jeddah, Alkamil, Kingdom of Saudi Arabia
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Tvrdý V, Pourová J, Jirkovský E, Křen V, Valentová K, Mladěnka P. Systematic review of pharmacokinetics and potential pharmacokinetic interactions of flavonolignans from silymarin. Med Res Rev 2021; 41:2195-2246. [PMID: 33587317 DOI: 10.1002/med.21791] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/06/2021] [Accepted: 01/29/2021] [Indexed: 12/15/2022]
Abstract
Silymarin is an extract from the seeds (fruits) of Silybum marianum that contains flavonolignans and flavonoids. Although it is frequently used as a hepatoprotective agent, its application remains somewhat debatable, in particular, due to the low oral bioavailability of flavonolignans. Moreover, there are claims of its potential interactions with concomitantly used drugs. This review aims at a systematic summary and critical assessment of known information on the pharmacokinetics of particular silymarin flavonolignans. There are two known major reasons for poor systemic oral bioavailability of flavonolignans: (1) rapid conjugation in intestinal cells or the liver and (2) efflux of parent flavonolignans or formed conjugates back to the lumen of the gastrointestinal tract by intestinal cells and rapid excretion by the liver into the bile. The metabolism of phase I appears to play a minor role, in contrast to extensive conjugation and indeed the unconjugated flavonolignans reach low plasma levels after common doses. Only about 1%-5% of the administered dose is eliminated by the kidneys. Many in vitro studies tested the inhibitory potential of silymarin and its components toward different enzymes and transporters involved in the absorption, metabolism, and excretion of xenobiotics. In most cases, effective concentrations are too high to be relevant under real biological conditions. Most human studies showed no silymarin-drug interactions explainable by these suggested interferences. More interactions were found in animal studies, likely due to the much higher doses administered.
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Affiliation(s)
- Václav Tvrdý
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Jana Pourová
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Eduard Jirkovský
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Vladimír Křen
- Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Kateřina Valentová
- Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Přemysl Mladěnka
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
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Lynch KD, Montonye ML, Tian DD, Arman T, Oyanna VO, Bechtold BJ, Graf TN, Oberlies NH, Paine MF, Clarke JD. Hepatic organic anion transporting polypeptides mediate disposition of milk thistle flavonolignans and pharmacokinetic silymarin-drug interactions. Phytother Res 2021; 35:3286-3297. [PMID: 33587330 PMCID: PMC8217340 DOI: 10.1002/ptr.7049] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/23/2020] [Accepted: 01/21/2021] [Indexed: 01/17/2023]
Abstract
Silybum marianum (L.) Gaertn. (Asteraceae), commonly known as milk thistle, is a botanical natural product used to self-treat multiple diseases such as Type 2 diabetes mellitus and nonalcoholic steatohepatitis (NASH). An extract from milk thistle seeds (achenes), termed silymarin, is comprised primarily of several flavonolignans. Systemic concentrations of these flavonolignans can influence the potential biologic effects of silymarin and the risk for pharmacokinetic silymarin-drug interactions. The aims of this research were to determine the roles of organic anion transporting polypeptides (OATPs/Oatps) in silymarin flavonolignan disposition and in pharmacokinetic silymarin-drug interactions. The seven major flavonolignans from silymarin were determined to be substrates for OATP1B1, OATP1B3, and OATP2B1. Sprague Dawley rats were fed either a control diet or a NASH-inducing diet and administered pitavastatin (OATP/Oatp probe substrate), followed by silymarin via oral gavage. Decreased protein expression of Oatp1b2 and Oatp1a4 in NASH animals increased flavonolignan area under the plasma concentration-time curve (AUC) and maximum plasma concentration. The combination of silymarin inhibition of Oatps and NASH-associated decrease in Oatp expression caused an additive increase in plasma pitavastatin AUC in the animals. These data indicate that OATPs/Oatps contribute to flavonolignan cellular uptake and mediate the interaction between silymarin and NASH on pitavastatin systemic exposure.
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Affiliation(s)
- Katherine D. Lynch
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Michelle L. Montonye
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Dan-Dan Tian
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Tarana Arman
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Victoria O. Oyanna
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Baron J. Bechtold
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Tyler N. Graf
- Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina
| | - Nicholas H. Oberlies
- Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina
| | - Mary F. Paine
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - John D. Clarke
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington
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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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9
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Bektur Aykanat NE, Kacar S, Karakaya S, Sahinturk V. Silymarin suppresses HepG2 hepatocarcinoma cell progression through downregulation of Slit-2/Robo-1 pathway. Pharmacol Rep 2020; 72:199-207. [PMID: 32016841 DOI: 10.1007/s43440-019-00040-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/19/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND 14 million people are diagnosed with new cancer and approximately 8 million people die from cancer every year. Hepatocellular carcinoma is the most common type of liver cancer and covers almost 5-6% of cancer deaths worldwide. Silybum marianum, a plant that contains silymarin, has been used traditionally in the treatment of liver diseases for centuries. The antioxidant, anti-inflammatory and anti-fibrotic anti-cancer properties of silymarin have been demonstrated in several studies in vivo and in vitro. The Slit/Robo signaling pathway plays a role in many processes such as neurogenesis, angiogenesis, cell proliferation, cell movement, cancer progression, cell invasion, migration and metastasis. In this study, we aimed to investigate the effects of silymarin on HepG2 Hepatocellular carcinoma cells on Slit-2/Robo-1 signaling pathway and CXCR-4 which plays a role in the metastasis process. METHODS HepG2 Hepatocellular carcinoma cells were used in the study. Different doses of silymarin's effect on HepG2 cells were observed by hematoxylin and eosin staining. Immunoblotting techniques were used to test the expression of Slit-2/Robo-1 and CXCR4 protein level. Immunocytochemistry was used to visualize the localization of Slit-2/Robo-1 and CXCR4 protein within the cells. RESULTS Silymarin caused apoptosis in HepG2 cells, decreased the level of CXCR-4 protein dose-dependently, and decreased the Slit-2/Robo-1 protein level at low doses and increased it at high doses. CONCLUSIONS Silymarin doses showed anti-carcinogenic, anti-metastatic and apoptotic effects in a dose-dependent manner on HepG2 cells through the Slit-2/Robo-1 pathway.
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Affiliation(s)
- Nuriye Ezgi Bektur Aykanat
- Department of Histology and Embryology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey.
| | - Sedat Kacar
- Department of Histology and Embryology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Serife Karakaya
- Department of Histology and Embryology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Varol Sahinturk
- Department of Histology and Embryology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
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Shi T, Wu L, Ma W, Ju L, Bai M, Chen X, Liu S, Yang X, Shi J. Nonalcoholic Fatty Liver Disease: Pathogenesis and Treatment in Traditional Chinese Medicine and Western Medicine. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:8749564. [PMID: 31998400 PMCID: PMC6969649 DOI: 10.1155/2020/8749564] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 11/14/2019] [Accepted: 11/20/2019] [Indexed: 01/30/2023]
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) is one of the most important causes of liver disease worldwide and probably destined to become the leading cause of end-stage liver disease in the coming decades, affecting both adults and children. Faced with the severe challenges for the prevention and control of NAFLD, this article discusses the understanding and mechanism of NAFLD from Chinese and Western medicine. Moreover, the progress regarding its treatment in both Chinese and Western medicine is also summarized. Both Chinese medicine and Western medicine have their own characteristics and clinical efficacy advantages in treating diseases. The purpose of this article is to hope that Chinese and Western medicine have complementary advantages, complementing each other to improve clinical NAFLD therapy prevention and treatment methods to receive more and more attention throughout the global medical community.
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Affiliation(s)
- Tingting Shi
- The Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310023, Zhejiang, China
| | - Li Wu
- Center of Clinical Evaluation, The First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Hangzhou 310006, Zhejiang, China
| | - Wenjun Ma
- The Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310023, Zhejiang, China
| | - Liping Ju
- The Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310023, Zhejiang, China
| | - Minghui Bai
- The Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310023, Zhejiang, China
| | - Xiaowei Chen
- The Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310023, Zhejiang, China
| | - Shourong Liu
- The Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou 310023, Zhejiang, China
| | - Xingxin Yang
- College of Pharmaceutical Science, Yunnan University of Traditional Chinese Medicine, 1076 Yuhua Road, Kunming 650500, Yunnan, China
| | - Junping Shi
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
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11
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Montonye ML, Tian DD, Arman T, Lynch KD, Hagenbuch B, Paine MF, Clarke JD. A Pharmacokinetic Natural Product-Disease-Drug Interaction: A Double Hit of Silymarin and Nonalcoholic Steatohepatitis on Hepatic Transporters in a Rat Model. J Pharmacol Exp Ther 2019; 371:385-393. [PMID: 31420525 PMCID: PMC6800447 DOI: 10.1124/jpet.119.260489] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 08/14/2019] [Indexed: 12/19/2022] Open
Abstract
Patients with nonalcoholic steatohepatitis (NASH) exhibit altered hepatic protein expression of metabolizing enzymes and transporters and altered xenobiotic pharmacokinetics. The botanical natural product silymarin, which has been investigated as a treatment of NASH, contains flavonolignans that inhibit organic anion-transporting polypeptide (OATP) transporter function. The purpose of this study was to assess the individual and combined effects of NASH and silymarin on the disposition of the model OATP substrate pitavastatin. Male Sprague Dawley rats were fed a control or a methionine- and choline-deficient diet (NASH model) for 8 weeks. Silymarin (10 mg/kg) or vehicle followed by pitavastatin (0.5 mg/kg) were administered intravenously, and the pharmacokinetics were determined. NASH increased mean total flavonolignan area under the plasma concentration-time curve (AUC0-120 min) 1.7-fold. Silymarin increased pitavastatin AUC0-120 min in both control and NASH animals approx. 2-fold. NASH increased pitavastatin plasma concentrations from 2 to 40 minutes, but AUC0-120 min was unchanged. The combination of silymarin and NASH had the greatest effect on pitavastatin AUC0-120 min, which increased 2.9-fold compared with control vehicle-treated animals. NASH increased the total amount of pitavastatin excreted into the bile 2.7-fold compared with control animals, whereas silymarin decreased pitavastatin biliary clearance approx. 3-fold in both control and NASH animals. This double hit of NASH and silymarin on hepatic uptake transporters is another example of a multifactorial pharmacokinetic interaction that may have a greater impact on drug disposition than each hit alone. SIGNIFICANCE STATEMENT: Multifactorial effects on xenobiotic pharmacokinetics are within the next frontier for precision medicine research and clinical application. The combination of silymarin and NASH is a probable clinical scenario that can affect drug uptake, liver concentrations, biliary elimination, and ultimately, efficacy and toxicity.
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Affiliation(s)
- Michelle L Montonye
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.L.M., D.-D.T., T.A., K.D.L., M.F.P., J.D.C.) and Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
| | - Dan-Dan Tian
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.L.M., D.-D.T., T.A., K.D.L., M.F.P., J.D.C.) and Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
| | - Tarana Arman
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.L.M., D.-D.T., T.A., K.D.L., M.F.P., J.D.C.) and Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
| | - Katherine D Lynch
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.L.M., D.-D.T., T.A., K.D.L., M.F.P., J.D.C.) and Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
| | - Bruno Hagenbuch
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.L.M., D.-D.T., T.A., K.D.L., M.F.P., J.D.C.) and Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
| | - Mary F Paine
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.L.M., D.-D.T., T.A., K.D.L., M.F.P., J.D.C.) and Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
| | - John D Clarke
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (M.L.M., D.-D.T., T.A., K.D.L., M.F.P., J.D.C.) and Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
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12
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Xie Y, Zhang D, Zhang J, Yuan J. Metabolism, Transport and Drug-Drug Interactions of Silymarin. Molecules 2019; 24:E3693. [PMID: 31615114 PMCID: PMC6832356 DOI: 10.3390/molecules24203693] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/11/2019] [Accepted: 10/14/2019] [Indexed: 02/07/2023] Open
Abstract
Silymarin, the extract of milk thistle, and its major active flavonolignan silybin, are common products widely used in the phytotherapy of liver diseases. They also have promising effects in protecting the pancreas, kidney, myocardium, and the central nervous system. However, inconsistent results are noted in the different clinical studies due to the low bioavailability of silymarin. Extensive studies were conducted to explore the metabolism and transport of silymarin/silybin as well as the impact of its consumption on the pharmacokinetics of other clinical drugs. Here, we aimed to summarize and highlight the current knowledge of the metabolism and transport of silymarin. It was concluded that the major efflux transporters of silybin are multidrug resistance-associated protein (MRP2) and breast cancer resistance protein (BCRP) based on results from the transporter-overexpressing cell lines and MRP2-deficient (TR-) rats. Nevertheless, compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin. Although silymarin does inhibit certain drug-metabolizing enzymes and drug transporters, such effects are unlikely to manifest in clinical settings. Overall, silymarin is a safe and well-tolerated phytomedicine.
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Affiliation(s)
- Ying Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macao 999078, China.
| | - Dingqi Zhang
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macao 999078, China.
| | - Jin Zhang
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macao 999078, China.
| | - Jialu Yuan
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macao 999078, China.
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13
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Radko L, Cybulski W. The decrease of lasalocid residue in the edible tissues by silymarin supplementation of chicken diet. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2019; 36:722-728. [PMID: 30973080 DOI: 10.1080/19440049.2019.1584406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Widespread use of coccidiostats, in spite of beneficial control of protozoan infections in poultry, implies a risk of residues in edible tissues, and there is increasing interest in the development of strategies for prevention of veterinary drugs residue in food-producing animals. The aim of this study is assigned to clarify the impact of silymarin addendum in the diet on lasalocid concentration in the liver and breast muscles from the broiler. Four groups of chickens received a feed with lasalocid at levels between 75 and 200 mg kg-1. Other four groups received a feed with lasalocid (75-200 mg kg-1) plus silymarin. Significant differences of lasalocid concentrations between the liver and breast muscles were observed. Moreover, the chickens from the groups supplemented with silymarin shown significant decreases of lasalocid concentrations in the analysed tissues. The herbal substance did not counteract the ionophore in the treatment of coccidiosis and did not change biochemical parameters of blood. These findings suggest that silymarin might be used in chicken feeding in order to reduce the risk from lasalocid contamination of the broiler edible tissues.
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Affiliation(s)
- Lidia Radko
- a Department of Pharmacology and Toxicology , National Veterinary Research Institute , Pulawy , Poland
| | - Wojciech Cybulski
- a Department of Pharmacology and Toxicology , National Veterinary Research Institute , Pulawy , Poland
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14
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Abenavoli L, Izzo AA, Milić N, Cicala C, Santini A, Capasso R. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res 2018; 32:2202-2213. [PMID: 30080294 DOI: 10.1002/ptr.6171] [Citation(s) in RCA: 253] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 07/06/2018] [Accepted: 07/09/2018] [Indexed: 12/17/2022]
Abstract
Milk thistle (MT; Silybum marianum), a member of the Asteraceae family, is a therapeutic herb with a 2,000-year history of use. MT fruits contain a mixture of flavonolignans collectively known as silymarin, being silybin (also named silibinin) the main component. This article reviews the chemistry of MT, the pharmacokinetics and bioavailability, the pharmacologically relevant actions for liver diseases (e.g., anti-inflammatory, immunomodulating, antifibrotic, antioxidant, and liver-regenerating properties) as well as the clinical potential in patients with alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, drug-induced liver injury, and mushroom poisoning. Overall, literature data suggest that, despite encouraging preclinical data, further well-designed randomized clinical trials are needed to fully substantiate the real value of MT preparations in liver diseases.
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, Catanzaro, Italy
| | - Angelo A Izzo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Natasa Milić
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Carla Cicala
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Antonello Santini
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
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15
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Chen P, Shang A, Wang W, Yang J. Astragaloside suppresses tumor necrosis factor receptor‐associated factor 5 signaling pathway and alleviates neurodegenerative changes in retinal pigment epithelial cells induced by isoflurane. J Cell Biochem 2018; 120:1028-1037. [PMID: 30277612 DOI: 10.1002/jcb.27599] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 08/08/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Pei‐Jun Chen
- Department of Anesthesiology The First Affiliated Hospital of Soochow University Suzhou China
- Department of Anesthesiology The Sixth People’s Hospital of Yancheng City Yancheng China
| | - An‐Quan Shang
- Department of Laboratory Medicine Tongji Hospital of Tongji University School of Medicine Shanghai China
| | - Wei‐Wei Wang
- Department of Pathology The Sixth People’s Hospital of Yancheng City Yancheng China
| | - Jian‐Ping Yang
- Department of Anesthesiology The First Affiliated Hospital of Soochow University Suzhou China
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The Bioavailability and Pharmacokinetics of Silymarin SMEDDS Formulation Study in Healthy Thai Volunteers. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:1507834. [PMID: 30108644 PMCID: PMC6077530 DOI: 10.1155/2018/1507834] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 07/09/2018] [Indexed: 02/06/2023]
Abstract
The present study aimed to determine the pharmacokinetic parameters and bioavailability of silymarin 140 mg SMEDDS formulation. An open-label, single-dose pharmacokinetic study was conducted. Twelve healthy volunteers were included in the study. After the volunteers had fasted overnight for 10 h, a single-dose generic silymarin 140 mg SMEDDS soft capsule was administered. Then 10 ml blood samples were taken at 0.0, 0.25, 0.50, 0.75, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, and 12.0 h. The plasma silybin concentrations were analyzed using validated LC-MS/MS. The pharmacokinetic parameters were analyzed and calculated. The pharmacokinetic parameters were calculated after silymarin had been administered as a single capsule. The mean (range) Cmax was 812.43 (259.47–1505.47) ng/ml at 0.80 (0.25–1.67) h (tmax). The mean (range) AUC0-t and AUC0-inf were 658.80 (268.29–1045.01) ng.h/ml and 676.98 (274.10–1050.96) ng.h/ml, respectively. The mean ke and t1/2 were 0.5386 h−1 and 1.91 h, respectively. The silymarin SMEDDS formulation soft capsule showed rapid absorption and high oral bioavailability.
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17
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Li Y, Guo S, Ren Q, Wei D, Zhao M, Su S, Tang Z, Duan JA. Pharmacokinetic Comparisons of Multiple Triterpenic Acids from Jujubae Fructus Extract Following Oral Delivery in Normal and Acute Liver Injury Rats. Int J Mol Sci 2018; 19:ijms19072047. [PMID: 30011885 PMCID: PMC6073449 DOI: 10.3390/ijms19072047] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 07/10/2018] [Accepted: 07/11/2018] [Indexed: 12/16/2022] Open
Abstract
Jujubae Fructus, the dried fruit of Ziziphus jujuba, has been used as Chinese medicine and food for centuries. Triterpenic acids have been found to be the major bioactive constituents in Jujubae Fructus responsible for their hepatoprotective activity in previous phytochemical and biological studies, while few pharmacokinetic studies have been conducted. To reveal the kinetics of the triterpenic acids under the pathological liver injury state, an established ultra-performance liquid chromatography coupled with a mass spectrometry method was applied for the simultaneous quantitation of seven triterpenic acids (ceanothic acid, epiceanothic acid, pomonic acid, alphitolic acid, maslinic acid, betulinic acid, and betulonic acid) in plasma samples of normal and acute liver injury rats induced by CCl₄. The results showed that there were significant differences (p < 0.05) in the pharmacokinetic parameters of seven triterpenic acids between model and normal groups. The AUC0–t and AUC0–∞ of epiceanothic acid (5227 ± 334 μg⋅h/L vs. 1478 ± 255 μg ⋅ h/L and 6127 ± 423 μg ⋅ h/L vs. 1482 ± 255 μg ⋅ h/L, respectively) and pomonic acid (4654 ± 349 μg ⋅ h/L vs. 1834 ± 225 μg ⋅ h/L and 4776 ± 322 μg ⋅ h/L vs. 1859 ± 230 μg ⋅ h/L, respectively) in model rats were significantly higher than those in normal rats, and the CLz/F of them were significantly decreased (0.28 ± 0.02 L/h/kg vs. 1.36 ± 0.18 L/h/kg and 19.96 ± 1.30 L/h/kg vs. 53.15 ± 5.60 L/h/kg, respectively). In contrast, the above parameters for alphitolic acid, betulinic acid and betulonic acid exhibited the quite different trend. This pharmacokinetic research might provide useful information for the clinical usage of triterpenic acids from Jujubae Fructus.
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Affiliation(s)
- Yao Li
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization/State Key Laboratory Cultivation Base for Traditional Chinese Medicine Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Sheng Guo
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization/State Key Laboratory Cultivation Base for Traditional Chinese Medicine Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Quanjin Ren
- Institute of Botany, Jiangsu Province and Chinese Academy of Science, Nanjing 210014, China.
| | - Dandan Wei
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization/State Key Laboratory Cultivation Base for Traditional Chinese Medicine Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Ming Zhao
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization/State Key Laboratory Cultivation Base for Traditional Chinese Medicine Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Shulan Su
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization/State Key Laboratory Cultivation Base for Traditional Chinese Medicine Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Zhishu Tang
- Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Jin-Ao Duan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization/State Key Laboratory Cultivation Base for Traditional Chinese Medicine Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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18
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de Avelar CR, Pereira EM, de Farias Costa PR, de Jesus RP, de Oliveira LPM. Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis. World J Gastroenterol 2017; 23:5004-5017. [PMID: 28785154 PMCID: PMC5526770 DOI: 10.3748/wjg.v23.i27.5004] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/06/2017] [Accepted: 06/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effect of silymarin on the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (γGT) in patients with liver diseases. METHODS A systematic review with meta-analysis of ramdomized and controlled clinical trials was performed, evaluating the effects of sylimarin in patients with hepatic diseases, published by January 31, 2016. Clinical trials were sought on the basis of The Cochrane Central Register of Controlled Trials in the Cochrane Library, PubMed/Medline, Scopus, Web of Science, Lilacs and Clinical Trials. The trials with adult and elderly patients of both sexes, with Liver Diseases who took oral silymarin supplementation, as extract or isolated, as well as Silymarin combined with other nutrients, were included. The trials should provide information about the intervention, such as dosages and detailing of the product used, besides the mean and standard deviation of serum levels of ALT, AST and γGT of the baseline and at the end of the intervention. RESULTS An amount of 10904 publications were identified. From those, only 17 were included in the systematic review and 6 in the meta-analysis, according to the used selection criteria. In this meta-analysis, the results indicated a reduction of 0.26 IU/mL (95%CI: -0.46-0.07, P = 0.007) at the level of ALT and 0.53 IU/mL (95%CI: -0.74-0.32, P = 0.000) at the serum levels of AST after using the silymarin, both, statistically significant, but with no clinical relevance. There was no significant change in the γGT levels. Subgroup analyzes were also performed for the biochemical markers in relation to the type of intervention, whether silymarin isolated or associated with other nutrients and the time of intervention (whether ≥ 6 mo or < 6 mo). Significant differences were not found. The evaluated studies presented a high degree of heterogeneity and low methodological quality in the carried out analysis. CONCLUSION Silymarin minimally reduced, but without clinical relevance, the serum levels of ALT and AST. It is necessary to carry out studies with more appropriate methodological designs.
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Hong M, Li S, Tan HY, Cheung F, Wang N, Huang J, Feng Y. A Network-Based Pharmacology Study of the Herb-Induced Liver Injury Potential of Traditional Hepatoprotective Chinese Herbal Medicines. Molecules 2017; 22:632. [PMID: 28420096 PMCID: PMC6154655 DOI: 10.3390/molecules22040632] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 04/06/2017] [Accepted: 04/12/2017] [Indexed: 12/15/2022] Open
Abstract
Herbal medicines are widely used for treating liver diseases and generally regarded as safe due to their extensive use in Traditional Chinese Medicine practice for thousands of years. However, in recent years, there have been increased concerns regarding the long-term risk of Herb-Induced Liver Injury (HILI) in patients with liver dysfunction. Herein, two representative Chinese herbal medicines: one-Xiao-Chai-Hu-Tang (XCHT)-a composite formula, and the other-Radix Polygoni Multiflori (Heshouwu)-a single herb, were analyzed by network pharmacology study. Based on the network pharmacology framework, we exploited the potential HILI effects of XCHT and Heshouwu by predicting the molecular mechanisms of HILI and identified the potential hepatotoxic ingredients in XCHT and Heshouwu. According to our network results, kaempferol and thymol in XCHT and rhein in Heshouwu exhibit the largest number of liver injury target connections, whereby CASP3, PPARG and MCL1 may be potential liver injury targets for these herbal medicines. This network pharmacology assay might serve as a useful tool to explore the underlying molecular mechanism of HILI. Based on the theoretical predictions, further experimental verification should be performed to validate the accuracy of the predicted interactions between herbal ingredients and protein targets in the future.
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Affiliation(s)
- Ming Hong
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Hor Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Fan Cheung
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Jihan Huang
- Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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20
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Comparative pharmacokinetics of bergenin, a main active constituent of Saxifraga stolonifera Curt., in normal and hepatic injury rats after oral administration. Chin J Nat Med 2017; 14:776-782. [PMID: 28236407 DOI: 10.1016/s1875-5364(16)30092-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Indexed: 01/28/2023]
Abstract
Bergenin, isolated from the herb of Saxifrage stolonifera Curt. (Hu-Er-Cao) has hepatoprotective, anti-inflammatory, antitussive, and neuroprotective activities. The aim of the present study was to establish a simple, rapid, and sensitive RP-HPLC method for determination of bergenin in rat plasma and compare its oral pharmacokinetic behaviors in normal and CCl4-induced hepatic injury rats. With norisoboldine as an internal standard, chromatographic separation was performed on a C18 analytical column with acetonitrile and water (11 : 89, V/V) containing 0.1% formic acid as the mobile phase. A good linearity was obtained over the range of 100-10 000 ng·mL-1. The lower limit of quantification was 50 ng·mL-1. The developed method was successfully applied to a study of the pharmacokinetic difference of bergenin (100 mg·kg-1) between normal and hepatic injury rats after oral administration. Marked alterations of pharmacokinetic parameters in hepatic injury rats were observed. Compared to normal rats, the AUC(0-∞) of bergenin in hepatic injury rats was elevated to 2.11-fold and Cmax was increased by 130%, whereas CL value was only 55% of the normal rats, suggesting that the systemic exposure of bergenin was significantly increased under hepatic injury status.
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21
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Xie Y, Miranda SR, Hoskins JM, Hawke RL. Role of UDP-Glucuronosyltransferase 1A1 in the Metabolism and Pharmacokinetics of Silymarin Flavonolignans in Patients with HCV and NAFLD. Molecules 2017; 22:E142. [PMID: 28098838 PMCID: PMC6155777 DOI: 10.3390/molecules22010142] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 12/30/2016] [Accepted: 01/08/2017] [Indexed: 02/06/2023] Open
Abstract
Silymarin is the most commonly used herbal medicine by patients with chronic liver disease. Silymarin flavonolignans undergo rapid first-pass metabolism primarily by glucuronidation. The aims of this investigation were: (1) to determine the association of UGT1A1*28 polymorphism with the area under the plasma concentration-time curves (AUCs) for silybin A (SA) and silybin B (SB); (2) to evaluate the effect of UGT1A1*28 polymorphism on the profile of flavonolignan glucuronide conjugates found in the plasma; and (3) to investigate the role of UGT1A1 enzyme kinetics on the pharmacokinetics of SA and SB. AUCs and metabolic ratios for thirty-three patients with chronic liver disease administered oral doses of silymarin were compared between different UGT1A1*28 genotypes. The AUCs, metabolic ratios, and the profiles of major SA and SB glucuronides did not differ significantly among the three UGT1A1 genotypes. In contrast, an increase in the proportion of sulfated flavonolignan conjugates in plasma was observed in subjects with UGT1A1*28/*28 genotype compared to subjects carrying wild type alleles. Differences in SA and SB in vitro intrinsic clearance estimates for UGTIA1 correlated inversely with SA and SB exposures observed in vivo indicating a major role for UGT1A1 in silymarin metabolism. In addition, a significant difference in the metabolic ratio observed between patients with NAFLD and HCV suggests that any effect of UGT1A1 polymorphism may be obscured by a greater effect of liver disease on the pharmacokinetics of silymarin. Taken together, these results suggest the presence of the UGT1A1*28 allele does not contribute significantly to a large inter-subject variability in the pharmacokinetics of silybin A and silybin B which may obscure the ability to detect beneficial effects of silymarin in patients with liver disease.
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Affiliation(s)
- Ying Xie
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China.
| | - Sonia R Miranda
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Janelle M Hoskins
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Roy L Hawke
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Hellerbrand C, Schattenberg JM, Peterburs P, Lechner A, Brignoli R. The potential of silymarin for the treatment of hepatic disorders. CLINICAL PHYTOSCIENCE 2016. [DOI: 10.1186/s40816-016-0019-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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A Comprehensive Updated Review of Pharmaceutical and Nonpharmaceutical Treatment for NAFLD. Gastroenterol Res Pract 2016; 2016:7109270. [PMID: 27006654 PMCID: PMC4781972 DOI: 10.1155/2016/7109270] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 01/27/2016] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the western world with prevalence of 20–33%. NAFLD comprises a pathological spectrum. Nonalcoholic fatty liver (NAFL) is at one end and consists of simple hepatic steatosis. On the contrary, nonalcoholic steatohepatitis (NASH) consists of steatosis, inflammation, and ballooning degeneration and can progress to cirrhosis. Despite the rising incidence, definitive treatment for NAFLD, specifically NASH, has not yet been established. Lifestyle modification with dietary changes combined with regular aerobic exercise, along with multidisciplinary approach including cognitive behavior therapy, has been shown to be an effective therapeutic option, even without a significant weight loss. Pioglitazone and vitamin E have shown to be most effective in NASH patients. Surgery and weight loss medication are effective means of weight loss but can potentially worsen NASH related fibrosis. Other agents such as n-3 polyunsaturated fatty acids, probiotics, and pentoxifylline along with herbal agent such as milk thistle as well as daily intake of coffee have shown potential benefits, but further well organized studies are definitely warranted. This review focuses on the available evidence on pharmaceutical and nonpharmaceutical therapy in the treatment and the prevention of NAFLD, primarily NASH.
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Liao S, Jin X, Li J, Zhang T, Zhang W, Shi W, Fan S, Wang X, Wang J, Zhong B, Zhang Z. Effects of Silymarin, Glycyrrhizin, and Oxymatrine on the Pharmacokinetics of Ribavirin and Its Major Metabolite in Rats. Phytother Res 2016; 30:618-26. [DOI: 10.1002/ptr.5567] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 12/06/2015] [Accepted: 12/10/2015] [Indexed: 01/18/2023]
Affiliation(s)
- Sha Liao
- State Key Laboratory of Toxicology and Medical Countermeasures; Beijing Institute of Pharmacology and Toxicology; 27 Taiping Road Beijing 100850 China
| | - Xueyuan Jin
- The International Therapy Center for Liver Disease; Military 302 Hospital; Beijing 100039 China
| | - Jinglai Li
- State Key Laboratory of Toxicology and Medical Countermeasures; Beijing Institute of Pharmacology and Toxicology; 27 Taiping Road Beijing 100850 China
| | - Tianhong Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures; Beijing Institute of Pharmacology and Toxicology; 27 Taiping Road Beijing 100850 China
| | - Wenpeng Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures; Beijing Institute of Pharmacology and Toxicology; 27 Taiping Road Beijing 100850 China
| | - Weiguo Shi
- State Key Laboratory of Toxicology and Medical Countermeasures; Beijing Institute of Pharmacology and Toxicology; 27 Taiping Road Beijing 100850 China
| | - Shiyong Fan
- State Key Laboratory of Toxicology and Medical Countermeasures; Beijing Institute of Pharmacology and Toxicology; 27 Taiping Road Beijing 100850 China
| | - Xiaoying Wang
- State Key Laboratory of Toxicology and Medical Countermeasures; Beijing Institute of Pharmacology and Toxicology; 27 Taiping Road Beijing 100850 China
| | - Juan Wang
- State Key Laboratory of Toxicology and Medical Countermeasures; Beijing Institute of Pharmacology and Toxicology; 27 Taiping Road Beijing 100850 China
| | - Bohua Zhong
- State Key Laboratory of Toxicology and Medical Countermeasures; Beijing Institute of Pharmacology and Toxicology; 27 Taiping Road Beijing 100850 China
| | - Zhenqing Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures; Beijing Institute of Pharmacology and Toxicology; 27 Taiping Road Beijing 100850 China
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ZAGOROVA M, PRASNICKA A, KADOVA Z, DOLEZELOVA E, KAZDOVA L, CERMANOVA J, ROZKYDALOVA L, HROCH M, MOKRY J, MICUDA S. Boldine Attenuates Cholestasis Associated With Nonalcoholic Fatty Liver Disease in Hereditary Hypertriglyceridemic Rats Fed by High-Sucrose Diet. Physiol Res 2015; 64:S467-76. [DOI: 10.33549/physiolres.933206] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The aim of the current study was to clarify the effect of high sucrose diet (HSD) on bile formation (BF) in rats with hereditary hypertriglyceridemia (HHTg). Potentially positive effects were studied for boldine, a natural choleretic agent. Administration of HSD to HHTg rats led to increased triglyceride deposition in the liver. HSD reduced BF as a consequence of decreased biliary secretion of bile acids (BA) and glutathione. Responsible mechanism was down-regulation of hepatic transporters for BA and glutathione, Bsep and Mrp2, respectively. Moreover, gene expressions of transporters for other constituents of bile, namely Abcg5/8 for cholesterol, Abcb4 for phospholipids, and Oatp1a4 for xenobiotics, were also reduced by HSD. Boldine partially attenuated cholestatic effect of HSD by promotion of biliary secretion of BA through up-regulation of Bsep and Ntcp, and by increase in biliary secretion of glutathione as a consequence of its increased hepatic disposition. This study demonstrates mechanisms of impaired BF during nonalcoholic fatty liver disease induced by HSD. Altered function of responsible transporters suggests also potential for changes in kinetics of drugs, which may complicate pharmacotherapy in subjects with high intake of sucrose, and with fatty liver disease. Sucrose induced alterations in BF may be alleviated by administration of boldine.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - S. MICUDA
- Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic
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Tan ZR, Zhou YX, Liu J, Huang WH, Chen Y, Wang YC, Wang LS. The influence of ABCB1 polymorphism C3435T on the pharmacokinetics of silibinin. J Clin Pharm Ther 2015; 40:685-8. [PMID: 26595166 DOI: 10.1111/jcpt.12336] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 10/12/2015] [Indexed: 12/23/2022]
Affiliation(s)
- Z. R. Tan
- Department of Clinical Pharmacology; Xiang Ya Hospital of Central South University; Chang Sha China
| | - Y. X. Zhou
- Department of Clinical Pharmacology; Xiang Ya Hospital of Central South University; Chang Sha China
| | - J. Liu
- Department of Clinical Pharmacology; Xiang Ya Hospital of Central South University; Chang Sha China
| | - W. H. Huang
- Department of Clinical Pharmacology; Xiang Ya Hospital of Central South University; Chang Sha China
| | - Y. Chen
- Department of Clinical Pharmacology; Xiang Ya Hospital of Central South University; Chang Sha China
| | - Y. C. Wang
- Department of Clinical Pharmacology; Xiang Ya Hospital of Central South University; Chang Sha China
| | - L. S. Wang
- Department of Clinical Pharmacology; Xiang Ya Hospital of Central South University; Chang Sha China
- Institute of Clinical Pharmacology; Central South University; Chang Sha China
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Domitrović R, Potočnjak I. A comprehensive overview of hepatoprotective natural compounds: mechanism of action and clinical perspectives. Arch Toxicol 2015; 90:39-79. [DOI: 10.1007/s00204-015-1580-z] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 08/11/2015] [Indexed: 12/22/2022]
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Gufford BT, Chen G, Vergara AG, Lazarus P, Oberlies NH, Paine MF. Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction. Drug Metab Dispos 2015; 43:1353-9. [PMID: 26070840 PMCID: PMC4538855 DOI: 10.1124/dmd.115.065086] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 06/12/2015] [Indexed: 12/26/2022] Open
Abstract
Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4'- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27-66 µM; UGT1A1, 3.2-8.3 µM; UGT1A8, 19-73 µM; and UGT1A10, 65-120 µM) encompassed reported intestinal tissue concentrations (20-310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product-drug interactions in the context of cancer prevention.
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Affiliation(s)
- Brandon T Gufford
- Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.)
| | - Gang Chen
- Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.)
| | - Ana G Vergara
- Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.)
| | - Philip Lazarus
- Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.)
| | - Nicholas H Oberlies
- Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.)
| | - Mary F Paine
- Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., A.G.V., P.L.), College of Pharmacy, Washington State University, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, North Carolina (N.H.O.)
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Chen CH, Chang CC, Shih TH, Aljuffali IA, Yeh TS, Fang JY. Self-nanoemulsifying drug delivery systems ameliorate the oral delivery of silymarin in rats with Roux-en-Y gastric bypass surgery. Int J Nanomedicine 2015; 10:2403-16. [PMID: 25848259 PMCID: PMC4381630 DOI: 10.2147/ijn.s79522] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Roux-en-Y gastric bypass (RYGB) is a popular surgery to reduce the body weight of obese patients. Although food intake is restricted by RYGB, drug absorption is also decreased. The purpose of this study was to develop novel self-nanoemulsifying drug delivery systems (SNEDDS) for enhancing the oral delivery of silymarin, which has poor water solubility. The SNEDDS were characterized by size, zeta potential, droplet number, and morphology. A technique of RYGB was performed in Sprague-Dawley rats. SNEDDS were administered at a silymarin dose of 600 mg/kg in normal and RYGB rats for comparison with silymarin aqueous suspension and polyethylene glycol (PEG) 400 solution. Plasma silibinin, the main active ingredient in silymarin, was chosen for estimating the pharmacokinetic parameters. SNEDDS diluted in simulated gastric fluid exhibited a droplet size of 190 nm with a spherical shape. The nanocarriers promoted silibinin availability via oral ingestion in RYGB rats by 2.5-fold and 1.5-fold compared to the suspension and PEG 400 solution, respectively. A significant double-peak concentration of silibinin was detected for RYGB rats receiving SNEDDS. Fluorescence imaging showed a deeper and broader penetration of Nile red, the fluorescence dye, into the gastrointestinal mucosa from SNEDDS than from PEG 400 solution. Histological examination showed that SNEDDS caused more minor inflammation at the gastrointestinal membrane as compared with that caused by PEG 400 solution, indicating a shielding of direct silymarin contact with the mucosa by the nanodroplets. SNEDDS generally showed low-level or negligible irritation in the gastrointestinal tract. Silymarin-loaded SNEDDS were successfully developed to improve the dissolution, permeability, and oral bioavailability of silymarin. To the best of our knowledge, this is the first investigation reporting the usefulness of SNEDDS for improving drug malabsorption elicited by gastric bypass surgery.
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Affiliation(s)
- Chun-Han Chen
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan ; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan
| | - Cheng-Chih Chang
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Tsung-Hsien Shih
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan
| | - Ibrahim A Aljuffali
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ta-Sen Yeh
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Kweishan, Taoyuan, Taiwan ; School of Medicine, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan
| | - Jia-You Fang
- Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan ; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan ; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan
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Kawaguchi-Suzuki M, Frye RF, Zhu HJ, Brinda BJ, Chavin KD, Bernstein HJ, Markowitz JS. The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. Drug Metab Dispos 2014; 42:1611-6. [PMID: 25028567 PMCID: PMC4164972 DOI: 10.1124/dmd.114.057232] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 07/15/2014] [Indexed: 01/08/2023] Open
Abstract
Milk thistle (Silybum marianum) extracts are widely used as a complementary and alternative treatment of various hepatic conditions and a host of other diseases/disorders. The active constituents of milk thistle supplements are believed to be the flavonolignans contained within the extracts. In vitro studies have suggested that some milk thistle components may significantly inhibit specific cytochrome P450 (P450) enzymes. However, determining the potential for clinically significant drug interactions with milk thistle products has been complicated by inconsistencies between in vitro and in vivo study results. The aim of the present study was to determine the effect of a standardized milk thistle supplement on major P450 drug-metabolizing enzymes after a 14-day exposure period. CYP1A2, CYP2C9, CYP2D6, and CYP3A4/5 activities were measured by simultaneously administering the four probe drugs, caffeine, tolbutamide, dextromethorphan, and midazolam, to nine healthy volunteers before and after exposure to a standardized milk thistle extract given thrice daily for 14 days. The three most abundant falvonolignans found in plasma, following exposure to milk thistle extracts, were silybin A, silybin B, and isosilybin B. The concentrations of these three major constituents were individually measured in study subjects as potential perpetrators. The peak concentrations and areas under the time-concentration curves of the four probe drugs were determined with the milk thistle administration. Exposure to milk thistle extract produced no significant influence on CYP1A2, CYP2C9, CYP2D6, or CYP3A4/5 activities.
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Affiliation(s)
- Marina Kawaguchi-Suzuki
- Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina
| | - Reginald F Frye
- Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina
| | - Hao-Jie Zhu
- Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina
| | - Bryan J Brinda
- Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina
| | - Kenneth D Chavin
- Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina
| | - Hilary J Bernstein
- Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina
| | - John S Markowitz
- Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina
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Vargas-Mendoza N, Madrigal-Santillán E, Morales-González A, Esquivel-Soto J, Esquivel-Chirino C, García-Luna Y González-Rubio M, Gayosso-de-Lucio JA, Morales-González JA. Hepatoprotective effect of silymarin. World J Hepatol 2014; 6:144-149. [PMID: 24672644 PMCID: PMC3959115 DOI: 10.4254/wjh.v6.i3.144] [Citation(s) in RCA: 238] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Revised: 01/27/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
The use of medicinal plants in treating illnesses has been reported since ancestral times. In the case of hepatic diseases, several species such as Silybum marianum, Phyllanthus niruri, and Panus giganteus (Berk.) have been shown to ameliorate hepatic lesions. Silymarin is a natural compound derived from the species Silybum marianum, which is commonly known as Milk thistle. This plant contains at least seven flavoligands and the flavonoid taxifolin. The hepatoprotective and antioxidant activity of silymarin is caused by its ability to inhibit the free radicals that are produced from the metabolism of toxic substances such as ethanol, acetaminophen, and carbon tetrachloride. The generation of free radicals is known to damage cellular membranes and cause lipoperoxidation. Silymarin enhances hepatic glutathione and may contribute to the antioxidant defense of the liver. It has also been shown that silymarin increases protein synthesis in hepatocytes by stimulating RNA polymerase I activity. A previous study on humans reported that silymarin treatment caused a slight increase in the survival of patients with cirrhotic alcoholism compared with untreated controls.
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Affiliation(s)
- Nancy Vargas-Mendoza
- Nancy Vargas-Mendoza, Juan A Gayosso-de-Lucio, Institute of Health Sciences, Autonomous University of Hidalgo State, Pachuca 42000, México
| | - Eduardo Madrigal-Santillán
- Nancy Vargas-Mendoza, Juan A Gayosso-de-Lucio, Institute of Health Sciences, Autonomous University of Hidalgo State, Pachuca 42000, México
| | - Angel Morales-González
- Nancy Vargas-Mendoza, Juan A Gayosso-de-Lucio, Institute of Health Sciences, Autonomous University of Hidalgo State, Pachuca 42000, México
| | - Jaime Esquivel-Soto
- Nancy Vargas-Mendoza, Juan A Gayosso-de-Lucio, Institute of Health Sciences, Autonomous University of Hidalgo State, Pachuca 42000, México
| | - Cesar Esquivel-Chirino
- Nancy Vargas-Mendoza, Juan A Gayosso-de-Lucio, Institute of Health Sciences, Autonomous University of Hidalgo State, Pachuca 42000, México
| | | | - Juan A Gayosso-de-Lucio
- Nancy Vargas-Mendoza, Juan A Gayosso-de-Lucio, Institute of Health Sciences, Autonomous University of Hidalgo State, Pachuca 42000, México
| | - José A Morales-González
- Nancy Vargas-Mendoza, Juan A Gayosso-de-Lucio, Institute of Health Sciences, Autonomous University of Hidalgo State, Pachuca 42000, México
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Brantley SJ, Argikar AA, Lin YS, Nagar S, Paine MF. Herb-drug interactions: challenges and opportunities for improved predictions. Drug Metab Dispos 2014; 42:301-17. [PMID: 24335390 PMCID: PMC3935140 DOI: 10.1124/dmd.113.055236] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 12/11/2013] [Indexed: 01/23/2023] Open
Abstract
Supported by a usage history that predates written records and the perception that "natural" ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb-drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb-drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb-drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb-drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens.
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Affiliation(s)
- Scott J Brantley
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (S.J.B.); Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania (A.A.A., S.N.); Department of Pharmaceutics, University of Washington, Seattle, Washington (Y.S.L.); and College of Pharmacy, Washington State University, Spokane, Washington (M.F.P.)
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Hackett ES, Mama KR, Twedt DC, Gustafson DL. Pharmacokinetics and safety of silibinin in horses. Am J Vet Res 2013; 74:1327-32. [PMID: 24066917 DOI: 10.2460/ajvr.74.10.1327] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
OBJECTIVE To determine the oral bioavailability, single and multidose pharmacokinetics, and safety of silibinin, a milk thistle derivative, in healthy horses. ANIMALS 9 healthy horses. PROCEDURES Horses were initially administered silibinin IV and silibinin phospholipid orally in feed and via nasogastric tube. Five horses then consumed increasing orally administered doses of silibinin phospholipid during 4 nonconsecutive weeks (0 mg/kg, 6.5 mg/kg, 13 mg/kg, and 26 mg/kg of body weight, twice daily for 7 days each week). RESULTS Bioavailability of orally administered silibinin phospholipid was 0.6% PO in feed and 2.9% via nasogastric tube. During the multidose phase, silibinin had nonlinear pharmacokinetics. Despite this, silibinin did not accumulate when given twice daily for 7 days at the evaluated doses. Dose-limiting toxicosis was not observed. CONCLUSIONS AND CLINICAL RELEVANCE Silibinin phospholipid was safe, although poorly bio-available, in horses. Further study is indicated in horses with hepatic disease.
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Affiliation(s)
- Eileen S Hackett
- Department of Clinical Sciences, College of Veterinary Medicine and Biological Sciences, Colorado State University, Fort Collins, CO, 80523
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Zhu HJ, Brinda BJ, Chavin KD, Bernstein HJ, Patrick KS, Markowitz JS. An assessment of pharmacokinetics and antioxidant activity of free silymarin flavonolignans in healthy volunteers: a dose escalation study. Drug Metab Dispos 2013; 41:1679-85. [PMID: 23835761 PMCID: PMC3876803 DOI: 10.1124/dmd.113.052423] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Accepted: 06/26/2013] [Indexed: 01/31/2023] Open
Abstract
Milk thistle (Silybum marianum) extracts, one of the most widely used dietary supplements, contain a mixture of six major flavonolignans (silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin) and other components. However, the pharmacokinetics of the free individual flavonolignans have been only partially investigated in humans. Furthermore, antioxidant effects of the extract, which may underlie the basis of many therapeutic effects, have not been thoroughly assessed. The present study evaluated the pharmacokinetics of the six major flavonolignans in healthy volunteers receiving single doses of either one (175 mg), two (350 mg), or three (525 mg) milk thistle capsule(s) on three separate study visits. Additionally, the steady-state pharmacokinetic parameters were determined after the subjects were administered one capsule three times daily for 28 consecutive days. Our results demonstrated that all six flavonolignans were rapidly absorbed and eliminated. In order of abundance, the exposure to free flavonolignans was greatest for silybin A followed by silybin B, isosilybin B, isosilybin A, silychristin, and silydianin. The systemic exposure to these compounds appeared linear and dose proportional. The disposition of flavonolignans was stereoselective, as evidenced by the apparent clearance of silybin B, which was significantly greater than silybin A, whereas the apparent clearance of isosilybin B was significantly lower than isosilybin A. The concentrations of urinary 8-epi-prostaglandin F2α, a commonly used biomarker of oxidative status in humans, were considerably decreased in study subjects after a 28-day exposure to the extract (1.3 ± 0.9 versus 0.8 ± 0.9 ng/mg creatinine) but failed to reach statistical significance (P = 0.076).
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Affiliation(s)
- Hao-Jie Zhu
- Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA
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Brantley SJ, Graf TN, Oberlies NH, Paine MF. A systematic approach to evaluate herb-drug interaction mechanisms: investigation of milk thistle extracts and eight isolated constituents as CYP3A inhibitors. Drug Metab Dispos 2013; 41:1662-70. [PMID: 23801821 PMCID: PMC3876807 DOI: 10.1124/dmd.113.052563] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Accepted: 06/25/2013] [Indexed: 10/26/2022] Open
Abstract
Despite increasing recognition of potential untoward interactions between herbal products and conventional medications, a standard system for prospective assessment of these interactions remains elusive. This information gap was addressed by evaluating the drug interaction liability of the model herbal product milk thistle (Silybum marianum) with the CYP3A probe substrate midazolam. The inhibitory effects of commercially available milk thistle extracts and isolated constituents on midazolam 1'-hydroxylation were screened using human liver and intestinal microsomes. Relative to vehicle, the extract silymarin and constituents silybin A, isosilybin A, isosilybin B, and silychristin at 100 μM demonstrated >50% inhibition of CYP3A activity with at least one microsomal preparation, prompting IC50 determination. The IC50s for isosilybin B and silychristin were ∼60 and 90 μM, respectively, whereas those for the remaining constituents were >100 μM. Extracts and constituents that contained the 1,4-dioxane moiety demonstrated a >1.5-fold shift in IC50 when tested as potential mechanism-based inhibitors. The semipurified extract, silibinin, and the two associated constituents (silybin A and silybin B) demonstrated mechanism-based inhibition of recombinant CYP3A4 (KI, ∼100 μM; kinact, ∼0.20 min(-1)) but not microsomal CYP3A activity. The maximum predicted increases in midazolam area under the curve using the static mechanistic equation and recombinant CYP3A4 data were 1.75-fold, which may necessitate clinical assessment. Evaluation of the interaction liability of single herbal product constituents, in addition to commercially available extracts, will enable elucidation of mechanisms underlying potential clinically significant herb-drug interactions. Application of this framework to other herbal products would permit predictions of herb-drug interactions and assist in prioritizing clinical evaluation.
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Affiliation(s)
- Scott J Brantley
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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36
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Gandhi A, Moorthy B, Ghose R. Drug disposition in pathophysiological conditions. Curr Drug Metab 2013; 13:1327-44. [PMID: 22746301 DOI: 10.2174/138920012803341302] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Revised: 04/04/2012] [Accepted: 04/19/2012] [Indexed: 12/19/2022]
Abstract
Expression and activity of several key drug metabolizing enzymes (DMEs) and transporters are altered in various pathophysiological conditions, leading to altered drug metabolism and disposition. This can have profound impact on the pharmacotherapy of widely used clinically relevant medications in terms of safety and efficacy by causing inter-individual variabilities in drug responses. This review article highlights altered drug disposition in inflammation and infectious diseases, and commonly encountered disorders such as cancer, obesity/diabetes, fatty liver diseases, cardiovascular diseases and rheumatoid arthritis. Many of the clinically relevant drugs have a narrow therapeutic index. Thus any changes in the disposition of these drugs may lead to reduced efficacy and increased toxicity. The implications of changes in DMEs and transporters on the pharmacokinetics/pharmacodynamics of clinically-relevant medications are also discussed. Inflammation-mediated release of pro-inflammatory cytokines and activation of toll-like receptors (TLRs) are known to play a major role in down-regulation of DMEs and transporters. Although the mechanism by which this occurs is unclear, several studies have shown that inflammation-associated cell-signaling pathway and its interaction with basal transcription factors and nuclear receptors in regulation of DMEs and transporters play a significant role in altered drug metabolism. Altered regulation of DMEs and transporters in a multitude of disease states will contribute towards future development of powerful in vitro and in vivo tools in predicting the drug response and opt for better drug design and development. The goal is to facilitate a better understanding of the mechanistic details underlying the regulation of DMEs and transporters in pathophysiological conditions.
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Affiliation(s)
- Adarsh Gandhi
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77030, USA
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37
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Polyak SJ, Ferenci P, Pawlotsky JM. Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepatology 2013; 57:1262-1271. [PMID: 23213025 PMCID: PMC3594650 DOI: 10.1002/hep.26179] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 09/05/2012] [Indexed: 12/21/2022]
Affiliation(s)
- Stephen J Polyak
- Department of Laboratory Medicine, University of Washington, Seattle, WA 98104, USA.
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38
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Hackett ES, Twedt DC, Gustafson DL. Milk thistle and its derivative compounds: a review of opportunities for treatment of liver disease. J Vet Intern Med 2013; 27:10-6. [PMID: 23140176 DOI: 10.1111/jvim.12002] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 08/18/2012] [Accepted: 09/18/2012] [Indexed: 02/06/2023] Open
Abstract
Milk thistle extracts have been used as a "liver tonic" for centuries. In recent years, silibinin, the active ingredient in milk thistle extracts, has been studied both in vitro and in vivo to evaluate the beneficial effects in hepatic disease. Silibinin increases antioxidant concentrations and improves outcomes in hepatic diseases resulting from oxidant injury. Silibinin treatment has been associated with protection against hepatic toxins, and also has resulted in decreased hepatic inflammation and fibrosis. Limited information currently is available regarding silibinin use in veterinary medicine. Future study is justified to evaluate dose, kinetics, and treatment effects in domestic animals.
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Affiliation(s)
- E S Hackett
- Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
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39
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Dunnick JK, Nyska A. The toxicity and pathology of selected dietary herbal medicines. Toxicol Pathol 2012; 41:374-86. [PMID: 23262639 DOI: 10.1177/0192623312466451] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Toxicity studies were conducted by the National Toxicology Program (NTP) to provide information on the potential for toxicity from long-term use of commonly used herbal medicines. Here, we review the findings from these NTP toxicology/carcinogenesis 2-year rodent studies of 7 commonly used herbs. In these studies, the individual herb or herbal product was administered to F344/N rats and B6C3F1 mice by oral administration for up to 2 years. The spectrum of carcinogenic responses ranged from no or equivocal evidence for carcinogenic activity (ginseng, milk thistle, and turmeric oleoresin) to a liver tumor response (ginkgo, goldenseal, kava), thyroid tumor response (ginkgo), or an intestinal tumor response (Aloe vera whole leaf nondecolorized extract). Different mechanisms may be involved in the occurrence of liver (ginkgo, goldenseal, and kava kava) and gastrointestinal toxicity (turmeric oleoresin and Aloe vera whole leaf nondecolorized extract), while the toxic lesion is the same. The results from these hazard identification toxicity/carcinogenesis studies along with those from ongoing National Institute of Health clinical trials of herbal medicines provide more complete information on the risks and benefits from herbal medicine use in the general population.
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Affiliation(s)
- June K Dunnick
- National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
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40
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Halegoua-De Marzio D, Kraft WK, Daskalakis C, Ying X, Hawke RL, Navarro VJ. Limited sampling estimates of epigallocatechin gallate exposures in cirrhotic and noncirrhotic patients with hepatitis C after single oral doses of green tea extract. Clin Ther 2012; 34:2279-2285.e1. [PMID: 23153661 DOI: 10.1016/j.clinthera.2012.10.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Revised: 10/26/2012] [Accepted: 10/26/2012] [Indexed: 11/18/2022]
Abstract
BACKGROUND Epigallocatechin-3-gallate (EGCG) has antiangiogenic, antioxidant, and antifibrotic properties that may have therapeutic potential for the treatment of cirrhosis induced by hepatitis C virus (HCV). However, cirrhosis might affect EGCG disposition and augment its reported dose-dependent hepatotoxic potential. OBJECTIVE The safety, tolerability, and disposition of a single oral dose of EGCG in cirrhotic patients with HCV were examined in an exploratory fashion. METHODS Eleven patients with hepatitis C and detectable viremia were enrolled. Four had Child-Pugh (CP) class A cirrhosis, 4 had Child-Pugh class B cirrhosis, and 3 were noncirrhotic. After a single oral dose of green tea extract 400 mg containing 94% pure EGCG, blood for EGCG levels and safety parameters was ascertained at 2, 4, and 10 hours. RESULTS C(max) and AUC to EGCG overlapped among the 3 groups, which suggests that the disposition of EGCG was not significantly altered in these patients with cirrhosis. CONCLUSIONS A single 400-mg oral dose of EGCG was safe and well tolerated by all of the patients in the study. These results provide guidance for the continued investigation of the long-term safety and antitumor potential of EGCG in cirrhotic patients with HCV.
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Affiliation(s)
- Dina Halegoua-De Marzio
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
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41
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Polyak SJ, Oberlies NH, Pécheur EI, Dahari H, Ferenci P, Pawlotsky JM. Silymarin for HCV infection. Antivir Ther 2012; 18:141-147. [PMID: 23011959 PMCID: PMC4076489 DOI: 10.3851/imp2402] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2012] [Indexed: 12/11/2022]
Abstract
Silymarin, an extract of milk thistle seeds, and silymarin-derived compounds have been considered hepatoprotective since the plant was first described in ancient times. Hepatoprotection is defined as several non-mutually exclusive biological activities including antiviral, antioxidant, anti-inflammatory and immunomodulatory functions. Despite clear evidence for silymarin-induced hepatoprotection in cell culture and animal models, evidence for beneficial effects in humans has been equivocal. This review will summarize the current state of knowledge on silymarin in the context of HCV infection. The information was collated from a recent workshop on silibinin in Germany.
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Affiliation(s)
- Stephen J Polyak
- Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
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42
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Schrieber SJ, Hawke RL, Wen Z, Smith PC, Reddy KR, Wahed AS, Belle SH, Afdhal NH, Navarro VJ, Meyers CM, Doo E, Fried MW. Differences in the disposition of silymarin between patients with nonalcoholic fatty liver disease and chronic hepatitis C. Drug Metab Dispos 2011; 39:2182-90. [PMID: 21865319 PMCID: PMC3226378 DOI: 10.1124/dmd.111.040212] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Accepted: 08/09/2011] [Indexed: 01/21/2023] Open
Abstract
Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single- and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC(0-8 h)) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC(0-8 h) was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC(0-8 h) (p < 0.05) and 42% lower C(max) (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients.
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Affiliation(s)
- Sarah J Schrieber
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599-7360, USA
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43
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Reddy KR, Belle SH, Fried MW, Afdhal N, Navarro VJ, Hawke RL, Wahed AS, Doo E, Meyers CM. Rationale, challenges, and participants in a Phase II trial of a botanical product for chronic hepatitis C. Clin Trials 2011; 9:102-12. [PMID: 22058086 PMCID: PMC3293174 DOI: 10.1177/1740774511427064] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Chronic hepatitis C is associated with significant morbidity and mortality as a consequence of progression to cirrhosis, hepatocellular carcinoma, and liver failure. Current treatment for chronic hepatitis C with pegylated interferon (IFN) and ribavirin is associated with suboptimal responses and numerous adverse effects. A number of botanical products have been used to treat hepatic disorders. Silymarin, extracted from the milk thistle plant, Silybum marianum (L) Gaertn. (Asteraceae), has been most widely used for various liver disorders, including chronic hepatitis C, B, and alcoholic liver disease. However, the safety and efficacy of silymarin have not been studied systematically in chronic hepatitis C. PURPOSE We describe our strategy for a phased approach for studying the impact of silymarin in hepatitis C, in the context of the unique challenges of botanical product clinical trials and the development of specific and curative antiviral therapy. METHODS This multicenter, randomized, double-masked, placebo-controlled trial was conducted with four clinical centers and a data-coordinating center in the United States, to assess the impact of silymarin therapy in patients with chronic hepatitis C who failed conventional antiviral therapy. RESULTS Key aspects relevant to performing clinical trials of botanical products include early identification of an appropriate product with standard product chemistry, acquisition of pharmacokinetic and dosing information, selection of the appropriate study group, and choosing rigorous outcome variables. POTENTIAL LIMITATIONS: Trial participants were chronic hepatitis C patients who were nonsustained virologic responders to IFN-based therapy; therefore, the findings are not generalizable to all hepatitis C populations. Further, alanine aminotransferase, a biochemical liver test, rather than hepatitis viral RNA or liver histology was the primary end point. CONCLUSIONS The challenges identified and addressed during development of this United States multicenter Phase II trial to evaluate silymarin for treatment of patients with chronic hepatitis C infection who had failed to respond successfully to previous IFN-based therapy are common and must be addressed to conduct rigorous trials of botanical products.
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Mohamed MEF, Frye RF. Inhibitory effects of commonly used herbal extracts on UDP-glucuronosyltransferase 1A4, 1A6, and 1A9 enzyme activities. Drug Metab Dispos 2011; 39:1522-8. [PMID: 21632963 PMCID: PMC3164271 DOI: 10.1124/dmd.111.039602] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Accepted: 06/01/2011] [Indexed: 12/12/2022] Open
Abstract
The aim of this study was to investigate the effect of commonly used botanicals on UDP-glucuronosyltransferase (UGT) 1A4, UGT1A6, and UGT1A9 activities in human liver microsomes. The extracts screened were black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, and valerian in addition to the green tea catechin epigallocatechin gallate (EGCG). Formation of trifluoperazine glucuronide, serotonin glucuronide, and mycophenolic acid phenolic glucuronide was used as an index reaction for UGT1A4, UGT1A6, and UGT1A9 activities, respectively, in human liver microsomes. Inhibition potency was expressed as the concentration of the inhibitor at 50% activity (IC(50)) and the volume in which the dose could be diluted to generate an IC(50)-equivalent concentration [volume/dose index (VDI)]. Potential inhibitors were EGCG for UGT1A4, milk thistle for both UGT1A6 and UGT1A9, saw palmetto for UGT1A6, and cranberry for UGT1A9. EGCG inhibited UGT1A4 with an IC(50) value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC(50) values of 59.5 ± 3.6 and 33.6 ± 3.1 μg/ml, respectively. Saw palmetto and cranberry weakly inhibited UGT1A6 and UGT1A9, respectively, with IC(50) values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC(50)-equivalent concentrations in vivo. VDI values for inhibitors indicate a potential for inhibition of first-pass glucuronidation of UGT1A4, UGT1A6, and UGT1A9 substrates. These results highlight the possibility of herb-drug interactions through modulation of UGT enzyme activities. Further clinical studies are warranted to investigate the in vivo extent of the observed interactions.
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Affiliation(s)
- Mohamed-Eslam F Mohamed
- Department of Pharmacotherapy and Translational Research, University of Florida, College of Pharmacy, Gainesville, FL 32610, USA
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Loguercio C, Festi D. Silybin and the liver: From basic research to clinical practice. World J Gastroenterol 2011; 17:2288-301. [PMID: 21633595 PMCID: PMC3098397 DOI: 10.3748/wjg.v17.i18.2288] [Citation(s) in RCA: 244] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2010] [Revised: 12/23/2010] [Accepted: 12/30/2010] [Indexed: 02/06/2023] Open
Abstract
Herbal products are increasingly used, mainly in chronic liver disease. Extracts of milk thistle, Silymarin and silybin, are the most prescribed natural compounds, with different indications, but with no definitive results in terms of clinical efficacy. This review analyzes the available studies on the effects of the purified product silybin, both as a free and a conjugated molecule, on liver cells or on experimentally induced liver damage, and in patients with liver disease. We searched PUBMED for articles pertaining to the in vitro and in vivo effects of silybin, its antifibrotic, anti-inflammatory, and antioxidant properties, as well as its metabolic effects, combined with the authors’ own knowledge of the literature. Results indicate that the bioavailability of silybin phytosome is higher than that of silymarin and is less influenced by liver damage; silybin does not show significant interactions with other drugs and at doses < 10 g/d has no significant side effects. Experimental studies have clearly demonstrated the antifibrotic, antioxidant and metabolic effects of silybin; previous human studies were insufficient for confirming the clinical efficacy in chronic liver disease, while ongoing clinical trials are promising. On the basis of literature data, silybin seems a promising drug for chronic liver disease.
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46
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Li P, Robertson TA, Thorling CA, Zhang Q, Fletcher LM, Crawford DHG, Roberts MS. Hepatic pharmacokinetics of cationic drugs in a high-fat emulsion-induced rat model of nonalcoholic steatohepatitis. Drug Metab Dispos 2011; 39:571-9. [PMID: 21245286 DOI: 10.1124/dmd.110.036806] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The hepatic pharmacokinetics of five selected cationic drugs (propranolol, labetalol, metoprolol, antipyrine, and atenolol) was studied in the liver from control rats and from those with high-fat emulsion-induced nonalcoholic steatohepatitis (NASH). Studies were undertaken using an in situ-perfused rat liver and multiple indicator dilution, and outflow data were analyzed with a physiologically based organ pharmacokinetic model. Hepatic extraction (E) was significantly lower in the NASH model, and lipophilicity was the main solute structural determinant of the observed differences in intrinsic elimination clearance (CL(int)) and permeability-surface area product (PS) with pK(a) defining the extent of sequestration in the liver [apparent distribution ratio (K(v))]. The main pathophysiological determinants were liver fibrosis, leading to a decreased PS, liver fat causing an increase in K(v), and an increase in both total liver cytochrome P450 (P450) concentration and P450 isoform expression for Cyp3a2 and Cyp2d2, causing an increase CL(int) in NASH rat livers compared with control livers. Changes in hepatic pharmacokinetics (PS, K(v), CL(int), and E ratio) as a result of NASH were related to the physicochemical properties of drugs (lipophilicity or pK(a)) and hepatic histopathological changes (fibrosis index, steatosis index, and P450 concentration) by stepwise regression analysis. Thus, it appears that in NASH, counteracting mechanisms to facilitate hepatic removal are created in NASH-induced P450 expression, whereas NASH-induced fibrosis and steatohepatitis inhibit E by decreasing hepatocyte permeability through fibrosis and hepatic sequestration.
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Affiliation(s)
- Peng Li
- Therapeutics Research Centre, School of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
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47
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Freedman ND, Curto TM, Morishima C, Seeff LB, Goodman ZD, Wright EC, Sinha R, Everhart JE, HALT-C Trial Group. Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial. Aliment Pharmacol Ther 2011; 33:127-37. [PMID: 21083592 PMCID: PMC3490214 DOI: 10.1111/j.1365-2036.2010.04503.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear. AIM To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment. METHODS Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes. RESULTS At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33-1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes. CONCLUSIONS Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).
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Affiliation(s)
- N D Freedman
- Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20852, USA.
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Blevins S, Siegel PB, Blodgett DJ, Ehrich M, Saunders GK, Lewis RM. Effects of silymarin on gossypol toxicosis in divergent lines of chickens. Poult Sci 2010; 89:1878-86. [PMID: 20709972 DOI: 10.3382/ps.2010-00768] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Gossypol, a pigment of cotton, is a hepatic toxin for chickens. Thus, despite its high protein content, inclusion of cottonseed meal in poultry diets is problematic. Silymarin, an extract from milk thistle, has hepatoprotective qualities and could potentially serve as a feed additive to offset the toxicity of gossypol. The objective of this study was to determine if silymarin could counteract gossypol toxicosis. Cockerels (n = 144) from lines divergently selected for humoral immunity were used. Three individuals from each line were randomly assigned to a cage and fed a corn-soybean meal (control) diet for 14 d. Six cages per line were then randomly assigned 1 of 4 dietary treatments (1,000 mg/kg of gossypol, 1,000 mg/kg of silymarin, 1,000 mg/kg of both gossypol and silymarin, or a control diet). Body weight and feed intake data were collected for 21 d, with chickens bled weekly to collect plasma and determine hematocrits. Chickens were then killed, and livers were collected for subsequent histology and enzymatic activity analyses. Endpoints measured weekly were analyzed with repeated measures and regression methodologies. Plasma and liver enzyme activities, and histological measures, were analyzed using ANOVA. No significant interactions between diets and lines were observed. Chickens assigned to the gossypol and gossypol-silymarin diets stopped gaining weight at d 14 (P < 0.001) and lost weight by d 21 (P < 0.001). Gamma glutamyltransferase was also elevated in these chickens at d 14; activities increased further by d 21 (P < 0.001). Histological examination of liver slices indicated substantial lipidosis (P < 0.001). Furthermore, quinone reductase activity was higher in gossypol- and gossypol-silymarin-treated chickens than in control and silymarin-treated chickens (P < 0.001). Silymarin did not alleviate any clinical effects of gossypol toxicosis.
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Affiliation(s)
- S Blevins
- Department of Animal and Poultry Sciences, Virginia Tech, Blacksburg, VA, USA
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Mohamed MEF, Tseng T, Frye RF. Inhibitory effects of commonly used herbal extracts on UGT1A1 enzyme activity. Xenobiotica 2010; 40:663-9. [PMID: 20666626 DOI: 10.3109/00498254.2010.505669] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Commonly used herbal supplements were screened for their potential to inhibit UGT1A1 activity using human liver microsomes. Extracts screened included ginseng, echinacea, black cohosh, milk thistle, garlic, valerian, saw palmetto, and green tea epigallocatechin gallate (EGCG). Estradiol-3-O-glucuronide (E-3-G) formation was used as the index of UGT1A1 activity. All herbal extracts except garlic showed inhibition of UGT1A1 activity at one or more of the three concentrations tested. A volume per dose index (VDI) was calculated to estimate the volume in which the daily dose should be diluted to obtain an IC(50)-equivalent concentration. EGCG, echinacea, saw palmetto, and milk thistle had VDI values >2.0 L per dose unit, suggesting a higher potential for interaction. Inhibition curves were constructed for EGCG, echinacea, saw palmetto, and milk thistle. IC(50) values were (mean ± SE) 7.8 ± 0.9, 211.7 ± 43.5, 55.2 ± 9.2, and 30.4 ± 6.9 µg/ml for EGCG, echinacea, saw palmetto, and milk thistle extracts, respectively. Based on our findings, inhibition of UGT1A1 by milk thistle and EGCG and to a lesser extent by echinacea and saw palmetto is plausible, particularly in the intestine where higher extract concentrations are anticipated. Further clinical studies are warranted.
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Affiliation(s)
- Mohamed-Eslam F Mohamed
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA
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Xie Y, Hao H, Kang A, Liang Y, Xie T, Sun S, Dai C, Zheng X, Xie L, Li J, Wang G. Integral pharmacokinetics of multiple lignan components in normal, CCl4-induced hepatic injury and hepatoprotective agents pretreated rats and correlations with hepatic injury biomarkers. JOURNAL OF ETHNOPHARMACOLOGY 2010; 131:290-299. [PMID: 20600750 DOI: 10.1016/j.jep.2010.06.038] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2010] [Revised: 06/18/2010] [Accepted: 06/23/2010] [Indexed: 05/29/2023]
Abstract
Although pharmacokinetic alternations by hepatic injury have been extensively studied, little is known about the potential influence of hepatoprotective agent's treatment. This study was aimed to investigate the holistic pharmacokinetics of multiple lignans, CYP3A regulations, and their correlations with hepatic injury biomarkers, in hepatic injured rats pretreated with or without schisandra lignan extract (SLE) and dimethyl-diphenyl-bicarboxylate (DDB). Integral pharmacokinetics of multiple lignans based on an AUC-weighting approach was determined in normal, CCl4 induced hepatic injury rats pretreated with or without SLE and DDB. Protein expression and activities of CYP3A were determined. Pharmacokinetic parameters and CYP3A activities were correlated with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. CCl4 induced acute hepatic injury resulted in a nearly 8-fold enhancement of integral plasma exposures of multiple lignans, which was caused by the significant down-regulation of CYP3A. SLE and DDB pretreatment exhibited potent hepatoprotective effects, accompanied with the restored expression and activity of CYP3A, and the recovery of the respective and integral pharmacokinetics of lignans components. The integral AUC(0-tn) and CYP3A activities correlated well with ALT and AST. This study suggested that the pharmacokinetic regulating effects of hepatoprotective agent's on themselves and co-prescribed drugs should be of concern, and hepatic injury biomarkers may serve as good predictors.
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Affiliation(s)
- Yuan Xie
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Key Unit of SATCM for Pharmacokinetic Methodology of TCM Complex Prescription, China Pharmaceutical University, Nanjing, China
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