|
1
|
Aurinsalo L, Lapatto‐Reiniluoto O, Kurkela M, Neuvonen M, Kiiski JI, Niemi M, Tornio A, Backman JT. A Phenotyping Tool for Seven Cytochrome P450 Enzymes and Two Transporters: Application to Examine the Effects of Clopidogrel and Gemfibrozil. Clin Pharmacol Ther 2025; 117:1732-1742. [PMID: 39982209 PMCID: PMC12087695 DOI: 10.1002/cpt.3610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/07/2025] [Indexed: 02/22/2025]
Abstract
Clinical cocktails for cytochrome P450 (CYP) phenotyping lack a marker for CYP2C8. We aimed to combine the CYP2C8 index drug repaglinide with the Geneva cocktail (caffeine/CYP1A2, bupropion/CYP2B6, flurbiprofen/CYP2C9, omeprazole/CYP2C19, dextromethorphan/CYP2D6, and midazolam/CYP3A4). We also included endogenous organic anion transporting polypeptide (OATP) 1B1 and 1B3 biomarkers glycochenodeoxycholate 3-O-glucuronide and glycochenodeoxycholate 3-sulfate, and investigated the CYP2C8 inhibition selectivity of clopidogrel and gemfibrozil with the full cocktail. In a five-phase randomized cross-over study, the following drugs were administered to 16 healthy volunteers: (i) repaglinide, (ii) the Geneva cocktail, (iii) repaglinide with the Geneva cocktail (full cocktail), (iv) clopidogrel followed by the full cocktail, and (v) gemfibrozil followed by the full cocktail. The Geneva cocktail increased repaglinide AUC0-23h 1.22-fold (90% confidence interval 1.04-1.44, P = 0.033). The full cocktail accurately captured known inhibitory effects of clopidogrel on CYP2B6, CYP2C8, and CYP2C19 and that of gemfibrozil on CYP2C8. Gemfibrozil decreased the paraxanthine/caffeine AUC0-12h ratio by 23% (14-31%, P < 0.01) and increased caffeine AUC0-12h 1.20-fold (1.03-1.40, P = 0.036). Gemfibrozil increased the metabolite-to-index drug AUC0-23h ratios of flurbiprofen, omeprazole, dextromethorphan, and midazolam 1.59-fold (1.32-1.92), 1.47-fold (1.34-1.61), 1.79-fold (1.23-2.59), and 2.1-fold (1.9-2.4), respectively, without affecting the index drug AUCs (P < 0.01). Gemfibrozil increased the AUC0-4h of glycochenodeoxycholate 3-O-glucuronide 1.33-fold (1.07-1.65, P = 0.027). In conclusion, the combination of repaglinide, the Geneva cocktail and endogenous biomarkers for OATP1B1 and OATP1B3 yields a nine-in-one phenotyping tool. Apart from strong CYP2C8 inhibition, gemfibrozil weakly inhibits CYP1A2 and OATP1B1 and appears to impair the elimination of the metabolites of several CYP index drugs.
Collapse
Affiliation(s)
- Laura Aurinsalo
- Department of Clinical PharmacologyUniversity of HelsinkiHelsinkiFinland
- Individualized Drug Therapy Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- Department of Clinical Pharmacology, HUS Diagnostic CenterHelsinki University HospitalHelsinkiFinland
| | - Outi Lapatto‐Reiniluoto
- Department of Clinical PharmacologyUniversity of HelsinkiHelsinkiFinland
- Individualized Drug Therapy Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- Department of Clinical Pharmacology, HUS Diagnostic CenterHelsinki University HospitalHelsinkiFinland
- HUS PharmacyHelsinki University HospitalHelsinkiFinland
| | - Mika Kurkela
- Department of Clinical PharmacologyUniversity of HelsinkiHelsinkiFinland
- Individualized Drug Therapy Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
| | - Mikko Neuvonen
- Department of Clinical PharmacologyUniversity of HelsinkiHelsinkiFinland
- Individualized Drug Therapy Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
| | - Johanna I. Kiiski
- Department of Clinical PharmacologyUniversity of HelsinkiHelsinkiFinland
- Individualized Drug Therapy Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
| | - Mikko Niemi
- Department of Clinical PharmacologyUniversity of HelsinkiHelsinkiFinland
- Individualized Drug Therapy Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- Department of Clinical Pharmacology, HUS Diagnostic CenterHelsinki University HospitalHelsinkiFinland
| | - Aleksi Tornio
- Integrative Physiology and Pharmacology, Institute of BiomedicineUniversity of TurkuTurkuFinland
- Unit of Clinical PharmacologyTurku University HospitalTurkuFinland
| | - Janne T. Backman
- Department of Clinical PharmacologyUniversity of HelsinkiHelsinkiFinland
- Individualized Drug Therapy Research Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- Department of Clinical Pharmacology, HUS Diagnostic CenterHelsinki University HospitalHelsinkiFinland
| |
Collapse
|
|
2
|
Shi Z, Han S. Personalized statin therapy: Targeting metabolic processes to modulate the therapeutic and adverse effects of statins. Heliyon 2025; 11:e41629. [PMID: 39866414 PMCID: PMC11761934 DOI: 10.1016/j.heliyon.2025.e41629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/31/2024] [Accepted: 01/01/2025] [Indexed: 01/28/2025] Open
Abstract
Statins are widely used for treating lipid disorders and cardiovascular diseases. However, the therapeutic efficiency and adverse effects of statins vary among different patients, which numerous clinical and epidemiological studies have attributed to genetic polymorphisms in statin-metabolizing enzymes and transport proteins. The metabolic processes of statins are relatively complex, involving spontaneous or enzyme-catalyzed interconversion between more toxic lactone metabolites and active acid forms in the liver and bloodstream, influenced by multiple factors, including the expression levels of many metabolic enzymes and transporters. Addressing the variable statin therapeutic outcomes is a pressing clinical challenge. Transcription factors and epigenetic modifications regulate the metabolic enzymes and transporters involved in statin metabolism and disposition and, therefore, hold promise as 'personalized' targets for achieving optimized statin therapy. In this review, we explore the potential for customizing therapy by targeting the metabolism of statin medications. The biochemical bases of adverse reactions to statin drugs and their correlation with polymorphisms in metabolic enzymes and transporters are summarized. Next, we mainly focus on the regulatory roles of transcription factors and epigenetic modifications in regulating the gene expression of statin biochemical machinery. The recommendations for future therapies are finally proposed by targeting the central regulatory factors of statin metabolism.
Collapse
Affiliation(s)
- Zhuangqi Shi
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, 830046, China
| | - Shuxin Han
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, 830046, China
| |
Collapse
|
|
3
|
Zeng W, Tomlinson B. Statin alternatives for the treatment of hypercholesterolemia - a safety evaluation. Expert Opin Drug Saf 2025; 24:17-24. [PMID: 39485240 DOI: 10.1080/14740338.2024.2424411] [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: 05/18/2024] [Revised: 09/19/2024] [Accepted: 10/28/2024] [Indexed: 11/03/2024]
Abstract
INTRODUCTION Statins are well established as the first-line treatment to reduce low-density-lipoprotein cholesterol (LDL-C) and cardiovascular (CV) events, but some patients are unable to tolerate effective doses or sometimes any dose of statins and alternative treatments may be required. AREAS COVERED In this review we summarize the relevant published literature obtained from a PubMed search on the safety of statin alternatives for the treatment of hypercholesterolemia. EXPERT OPINION The main alternatives to statins are ezetimibe, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab, alirocumab, and inclisiran, and the recently approved bempedoic acid. These have all shown an excellent safety profile and have not been associated with skeletal muscle symptoms or with increased risk of new onset diabetes and they have no major drug interactions. The injectable PCSK9 inhibitors are associated with a small increase in injection site reactions which are usually of mild or moderate intensity. Bempedoic acid is associated with a small increase in plasma uric acid and slightly increased frequency of episodes of gout in susceptible subjects. The cost and availability and the degree of lowering of LDL-C required are more likely to determine the choice of statin alternatives than the safety issues.
Collapse
Affiliation(s)
- Weiwei Zeng
- Department of Pharmacy, Shenzhen Longgang Second People's Hospital, Shenzhen, China
| | - Brian Tomlinson
- Faculty of Medicine, Macau University of Science & Technology, Macau, China
| |
Collapse
|
|
4
|
Ferri N, Colombo E, Corsini A. Bempedoic Acid, the First-in-Class Oral ATP Citrate Lyase Inhibitor with Hypocholesterolemic Activity: Clinical Pharmacology and Drug-Drug Interactions. Pharmaceutics 2024; 16:1371. [PMID: 39598495 PMCID: PMC11597693 DOI: 10.3390/pharmaceutics16111371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/22/2024] [Accepted: 10/22/2024] [Indexed: 11/29/2024] Open
Abstract
Bempedoic acid is a new drug that improves the control of cholesterol levels, either as monotherapy or in combination with existing lipid-lowering therapies, and shows clinical efficacy in cardiovascular disease patients. Thus, patients with comorbidities and under multiple therapies may be eligible for bempedoic acid, thus facing the potential problem of drug-drug interactions (DDIs). Bempedoic acid is a prodrug administered orally at a fixed daily dose of 180 mg. The dicarboxylic acid is enzymatically activated by conjugation with coenzyme A (CoA) to form the pharmacologically active thioester (bempedoic acid-CoA). This process is catalyzed by very-long-chain acyl-CoA synthetase 1 (ACSVL1), expressed almost exclusively at the hepatic level. Bempedoic acid-CoA is a potent and selective inhibitor of ATP citrate lyase (ACL), a key enzyme in the biosynthetic pathway of cholesterol and fatty acids. The drug reduces low-density lipoprotein-cholesterol (LDL-C) (20-25%), non-high-density lipoprotein-cholesterol (HDL-C) (19%), apolipoprotein B (apoB) (15%), and total cholesterol (16%) in patients with hypercholesterolemia or mixed dyslipidemia. The drug has a favorable pharmacokinetics profile. Bempedoic acid and its metabolites are not substrates or inhibitors/inducers of cytochrome P450 (CYP450) involved in drug metabolism. On the other hand, bempedoic acid-glucuronide is a substrate for organic anion transporter 3 (OAT3). Bempedoic acid and its glucuronide are weak inhibitors of the OAT2, OAT3, and organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Thus, bempedoic acid could inhibit (perpetrator) the hepatic uptake of OATP1B1/3 substrate drugs and the renal elimination of OAT2 and OAT3 substrates and could suffer (victim) the effect of OAT3 transporter inhibitors, reducing its renal elimination. Based on these pharmacological characteristics, here, we describe the potential DDIs of bempedoic acid with concomitant medications and the possible clinical implications.
Collapse
Affiliation(s)
- Nicola Ferri
- Department of Medicine, University of Padova, 35100 Padua, Italy
- Veneto Institute of Molecular Medicine, 35129 Padua, Italy
- Centro di Ricerca Coordinata sulle Interazioni Farmacologiche, 20122 Milan, Italy; (E.C.); (A.C.)
| | - Elisa Colombo
- Centro di Ricerca Coordinata sulle Interazioni Farmacologiche, 20122 Milan, Italy; (E.C.); (A.C.)
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, 20122 Milan, Italy
| | - Alberto Corsini
- Centro di Ricerca Coordinata sulle Interazioni Farmacologiche, 20122 Milan, Italy; (E.C.); (A.C.)
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, 20122 Milan, Italy
| |
Collapse
|
|
5
|
Kamimura T, Hounslow N, Suganami H, Tanigawa R. Drug-drug interactions between pemafibrate and statins on pharmacokinetics in healthy male volunteers: Open-label, randomized, 6-sequence, 3-period crossover studies. Clin Transl Sci 2024; 17:e13900. [PMID: 39078149 PMCID: PMC11287820 DOI: 10.1111/cts.13900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 07/02/2024] [Accepted: 07/12/2024] [Indexed: 07/31/2024] Open
Abstract
Elevated triglyceride levels are associated with an increased risk of cardiovascular events despite guideline-based statin treatment of low-density lipoprotein cholesterol. Peroxisome proliferator-activated receptor α (PPARα) agonists exert a significant triglyceride-lowering effect. However, combination therapy of PPARα agonists with statins poses an increased risk of rhabdomyolysis, which is rare but a major concern of the combination therapy. Pharmacokinetic interaction is suspected to be a contributing factor to the risk. To examine the potential for combination therapy with the selective PPARα modulator (SPPARMα) pemafibrate and statins, drug-drug interaction studies were conducted with open-label, randomized, 6-sequence, 3-period crossover designs for the combination of pemafibrate 0.2 mg twice daily and each of 6 statins once daily: pitavastatin 4 mg/day (n = 18), atorvastatin 20 mg/day (n = 18), rosuvastatin 20 mg/day (n = 29), pravastatin 20 mg/day (n = 18), simvastatin 20 mg/day (n = 20), and fluvastatin 60 mg/day (n = 19), involving healthy male volunteers. The pharmacokinetic parameters of pemafibrate and each of the statins were similar regardless of coadministration. There was neither an effect on the systemic exposure of pemafibrate nor a clinically important increase in the systemic exposure of any of the statins on the coadministration although the systemic exposure of simvastatin was reduced by about 15% and its open acid form by about 60%. The HMG-CoA reductase inhibitory activity in plasma samples from the simvastatin and pemafibrate combination group was about 70% of that in the simvastatin alone group. In conclusion, pemafibrate did not increase the systemic exposure of statins, and vice versa, in healthy male volunteers.
Collapse
Affiliation(s)
| | | | | | - Ryohei Tanigawa
- Global Clinical Development DepartmentKowa Company, Ltd.TokyoJapan
| |
Collapse
|
|
6
|
Miners JO, Polasek TM, Hulin JA, Rowland A, Meech R. Drug-drug interactions that alter the exposure of glucuronidated drugs: Scope, UDP-glucuronosyltransferase (UGT) enzyme selectivity, mechanisms (inhibition and induction), and clinical significance. Pharmacol Ther 2023:108459. [PMID: 37263383 DOI: 10.1016/j.pharmthera.2023.108459] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/03/2023]
Abstract
Drug-drug interactions (DDIs) arising from the perturbation of drug metabolising enzyme activities represent both a clinical problem and a potential economic loss for the pharmaceutical industry. DDIs involving glucuronidated drugs have historically attracted little attention and there is a perception that interactions are of minor clinical relevance. This review critically examines the scope and aetiology of DDIs that result in altered exposure of glucuronidated drugs. Interaction mechanisms, namely inhibition and induction of UDP-glucuronosyltransferase (UGT) enzymes and the potential interplay with drug transporters, are reviewed in detail, as is the clinical significance of known DDIs. Altered victim drug exposure arising from modulation of UGT enzyme activities is relatively common and, notably, the incidence and importance of UGT induction as a DDI mechanism is greater than generally believed. Numerous DDIs are clinically relevant, resulting in either loss of efficacy or an increased risk of adverse effects, necessitating dose individualisation. Several generalisations relating to the likelihood of DDIs can be drawn from the known substrate and inhibitor selectivities of UGT enzymes, highlighting the importance of comprehensive reaction phenotyping studies at an early stage of drug development. Further, rigorous assessment of the DDI liability of new chemical entities that undergo glucuronidation to a significant extent has been recommended recently by regulatory guidance. Although evidence-based approaches exist for the in vitro characterisation of UGT enzyme inhibition and induction, the availability of drugs considered appropriate for use as 'probe' substrates in clinical DDI studies is limited and this should be research priority.
Collapse
Affiliation(s)
- John O Miners
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia.
| | - Thomas M Polasek
- Certara, Princeton, NJ, USA; Centre for Medicines Use and Safety, Monash University, Melbourne, Australia
| | - Julie-Ann Hulin
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Andrew Rowland
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Robyn Meech
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
| |
Collapse
|
|
7
|
Liu J, Shi Y, Wu C, Hong B, Peng D, Yu N, Wang G, Wang L, Chen W. Comparison of Sweated and Non-Sweated Ethanol Extracts of Salvia miltiorrhiza Bge. (Danshen) Effects on Human and rat Hepatic UDP-Glucuronosyltransferase and Preclinic Herb-Drug Interaction Potential Evaluation. Curr Drug Metab 2022; 23:473-483. [PMID: 35585828 DOI: 10.2174/1389200223666220517115845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/16/2022] [Accepted: 03/08/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND The ethanol of Danshen (DEE) preparation has been widely used to treat cardiac-cerebral disease and cancer. Sweating is one of the primary processing methods of Danshen, which greatly influenced its quality and pharmacological properties. Sweated and non-sweated DEE preparation combining with various synthetic drugs, adding up the possibility of herbal-drug interactions. OBJECTIVE This study explored the effects of sweated and non-sweated DEE on human and rat hepatic UGT enzymes expression and activity and proposed a potential mechanism. METHODS The expression of two processed DEE on rat UGT1A, UGT2B and nuclear receptors including pregnane X receptor (PXR), constitutive androstane receptor (CAR), and peroxisome proliferator-activated receptor α (PPARα) were investigated after intragastric administration in rats by Western blot. Enzyme activity of DEE and its active ingredients (Tanshinone I, Cryptotanshinone, and Tanshinone I) on UGT isoenzymes was evaluated by quantifying probe substrate metabolism and metabolite formation in vitro using Ultra Performance Liquid Chromatography. RESULTS The two processed DEE (5.40 g/kg) improved UGT1A (P<0.01) and UGT2B (P<0.05) protein expression, and the non-sweated DEE (2.70 g/kg) upregulated UGT2B expression protein (P<0.05), compared with the CMCNa group. On day 28, UGT1A protein expression was increased (P<0.05) both in two processed DEE groups, meanwhile the non-sweated DEE significantly enhanced UGT2B protein expression (P<0.05) on day 21, compared with the CMCNa group. The process underlying this mechanism involved with the activation of nuclear receptors CAR, PXR, and PPARα; In vitro, sweated DEE (0-80 μg/mL) significantly inhibited the activity of human UGT1A7 (P<0.05) and rat UGT1A1, 1A8, and 1A9 (P<0.05). Non-sweated DEE (0-80 μg/mL) dramatically suppressed the activity of human UGT1A1, 1A3, 1A6, 1A7, 2B4, and 2B15, and rat UGT1A1, 1A3, 1A7, and 1A9 (P<0.05); Tanshinone I (0-1 μM) inhibited the activity of human UGT1A3, 1A6, and 1A7 (P<0.01) and rat UGT1A3, 1A6, 1A7, and 1A8 (P<0.05). Cryptotanshinone (0-1 μM) remarkably inhibited the activity of human UGT1A3 and 1A7 (P<0.05) and rat UGT1A7, 1A8, and 1A9 (P<0.05). Nonetheless, Tanshinone IIA (0-2 μM) is not a potent UGT inhibitor both in humans and rats; Additionally, there existed significant differences between two processed DEE in expression of PXR, and the activity of human UGT1A1, 1A3, 1A6, and 2B15 and rat UGT1A3 and 2B15 (P<0.05). CONCLUSION The effects of two processed DEE on hepatic UGT enzyme expression and activity were different. Accordingly, the combined usage of related UGTs substrates with DEE and its monomer components preparations may call for caution, depending on the drug's exposure-response relationship and dose adjustment. Besides, it is vital to pay attention to the distinction between sweated and non-sweated Danshen in clinic, which exerted an important influence on its pharmacological activity.
Collapse
Affiliation(s)
- Jie Liu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui,230012, China.,Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Traditional Chinese Medicine Decoction Pieces of New Manufacturing Technology, Anhui Hefei 230012, China
| | - Yun Shi
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui,230012, China.,Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Chengyuan Wu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui,230012, China.,Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Bangzhen Hong
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui,230012, China.,Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Daiyin Peng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui,230012, China.,Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Nianjun Yu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui,230012, China.,Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Guokai Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui,230012, China.,Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Lei Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui,230012, China.,Anhui Province Key Laboratory of Traditional Chinese Medicine Decoction Pieces of New Manufacturing Technology, Anhui Hefei 230012, China
| | - Weidong Chen
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui,230012, China.,Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China.,Anhui Province Key Laboratory of Traditional Chinese Medicine Decoction Pieces of New Manufacturing Technology, Anhui Hefei 230012, China
| |
Collapse
|
|
8
|
Ferraro RA, Leucker T, Martin SS, Banach M, Jones SR, Toth PP. Contemporary Management of Dyslipidemia. Drugs 2022; 82:559-576. [PMID: 35303294 PMCID: PMC8931779 DOI: 10.1007/s40265-022-01691-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2022] [Indexed: 12/30/2022]
Abstract
The treatment of dyslipidemia continues to be a dynamic and controversial topic. Even the most appropriate therapeutic range for lipid levels-including that of triglycerides and low-density lipoprotein cholesterol-remain actively debated. Furthermore, with ever-increasing options and available treatment modalities, the management of dyslipidemia has progressed in both depth and complexity. An understanding of appropriate lipid-lowering therapy remains an essential topic of review for practitioners across medical specialties. The goal of this review is to provide an overview of recent research developments and recommendations for patients with dyslipidemia as a means of better informing the clinical practice of lipid management. By utilizing a guideline-directed approach, we provide a reference point on optimal lipid-lowering therapies across the spectrum of dyslipidemia. Special attention is paid to long-term adherence to lipid-lowering therapies, and the benefits derived from instituting appropriate medications in a structured manner alongside monitoring. Novel therapies and their impact on lipid lowering are discussed in detail, as well as potential avenues for research going forward. The prevention of cardiovascular disease remains paramount, and this review provides a roadmap for instituting appropriate therapies in cardiovascular disease prevention.
Collapse
Affiliation(s)
- Richard A Ferraro
- From the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thorsten Leucker
- From the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Seth S Martin
- From the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz, Lodz, Poland
| | - Steven R Jones
- From the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Peter P Toth
- From the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- CGH Medical Center, 101 East Miller Road, Sterling, IL, 61081, USA.
| |
Collapse
|
|
9
|
Hammoud A, Shapiro MD. Drug Interactions: What Are Important Drug Interactions for the Most Commonly Used Medications in Preventive Cardiology? Med Clin North Am 2022; 106:389-399. [PMID: 35227438 DOI: 10.1016/j.mcna.2021.11.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Significant drug interactions contribute to hospitalizations, mortality, and health care costs. They often are preventable with a basic understanding of pharmacokinetics and pharmacodynamics. More than quarter of Americans above the age of 40 years take a statin, the most commonly used lipid-lowering therapy in modern times. Because of their pharmacokinetics, statins interact with numerous other drugs and substances, often in a manner that differs from statin to statin. This article provides an overview of important drug interactions for the most commonly used medications in preventive cardiology, with an emphasis on clinically significant interactions involving statins.
Collapse
Affiliation(s)
- Aziz Hammoud
- Section on Cardiovascular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Michael D Shapiro
- Section on Cardiovascular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Section on Cardiovascular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Center for Prevention of Cardiovascular Disease, Medical Center Boulevard, Winston Salem, NC 27157, USA.
| |
Collapse
|
|
10
|
Dubińska-Magiera M, Migocka-Patrzałek M, Lewandowski D, Daczewska M, Jagla K. Zebrafish as a Model for the Study of Lipid-Lowering Drug-Induced Myopathies. Int J Mol Sci 2021; 22:5654. [PMID: 34073503 PMCID: PMC8198905 DOI: 10.3390/ijms22115654] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/06/2021] [Accepted: 05/22/2021] [Indexed: 12/14/2022] Open
Abstract
Drug-induced myopathies are classified as acquired myopathies caused by exogenous factors. These pathological conditions develop in patients without muscle disease and are triggered by a variety of medicaments, including lipid-lowering drugs (LLDs) such as statins, fibrates, and ezetimibe. Here we summarise the current knowledge gained via studies conducted using various models, such as cell lines and mammalian models, and compare them with the results obtained in zebrafish (Danio rerio) studies. Zebrafish have proven to be an excellent research tool for studying dyslipidaemias as a model of these pathological conditions. This system enables in-vivo characterization of drug and gene candidates to further the understanding of disease aetiology and develop new therapeutic strategies. Our review also considers important environmental issues arising from the indiscriminate use of LLDs worldwide. The widespread use and importance of drugs such as statins and fibrates justify the need for the meticulous study of their mechanism of action and the side effects they cause.
Collapse
Affiliation(s)
- Magda Dubińska-Magiera
- Department of Animal Developmental Biology, Faculty of Biological Sciences, University of Wrocław, Sienkiewicza 21, 50-335 Wrocław, Poland; (M.D.-M.); (M.M.-P.); (D.L.)
| | - Marta Migocka-Patrzałek
- Department of Animal Developmental Biology, Faculty of Biological Sciences, University of Wrocław, Sienkiewicza 21, 50-335 Wrocław, Poland; (M.D.-M.); (M.M.-P.); (D.L.)
| | - Damian Lewandowski
- Department of Animal Developmental Biology, Faculty of Biological Sciences, University of Wrocław, Sienkiewicza 21, 50-335 Wrocław, Poland; (M.D.-M.); (M.M.-P.); (D.L.)
| | - Małgorzata Daczewska
- Department of Animal Developmental Biology, Faculty of Biological Sciences, University of Wrocław, Sienkiewicza 21, 50-335 Wrocław, Poland; (M.D.-M.); (M.M.-P.); (D.L.)
| | - Krzysztof Jagla
- Genetics Reproduction and Development Institute (iGReD), INSERM 1103, CNRS 6293, University of Clermont Auvergne, 28 Place Henri Dunant, 63001 Clermont-Ferrand, France
| |
Collapse
|
|
11
|
Corsini A, Ferri N, Proietti M, Boriani G. Edoxaban and the Issue of Drug-Drug Interactions: From Pharmacology to Clinical Practice. Drugs 2021; 80:1065-1083. [PMID: 32504376 DOI: 10.1007/s40265-020-01328-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Edoxaban, a direct factor Xa inhibitor, is the latest of the non-vitamin K antagonist oral anticoagulants (NOACs). Despite being marketed later than other NOACs, its use is now spreading in current clinical practice, being indicated for both thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF) and for the treatment and prevention of venous thromboembolism (VTE). In patients with multiple conditions, the contemporary administration of several drugs can cause relevant drug-drug interactions (DDIs), which can affect drugs' pharmacokinetics and pharmacodynamics. Usually, all the NOACs are considered to have significantly fewer DDIs than vitamin K antagonists; notwithstanding, this is actually not true, all of them are affected by DDIs with drugs that can influence the activity (induction or inhibition) of P-glycoprotein (P-gp) and cytochrome P450 3A4, both responsible for the disposition and metabolism of NOACs to a different extent. In this review/expert opinion, we focused on an extensive report of edoxaban DDIs. All the relevant drugs categories have been examined to report on significant DDIs, discussing the impact on edoxaban pharmacokinetics and pharmacodynamics, and the evidence for dose adjustment. Our analysis found that, despite a restrained number of interactions, some strong inhibitors/inducers of P-gp and drug-metabolising enzymes can affect edoxaban concentration, just as it happens with other NOACs, implying the need for a dose adjustment. However, our analysis of edoxaban DDIs suggests that given the small propensity for interactions of this agent, its use represents an acceptable clinical decision. Still, DDIs can be significant in certain clinical situations and a careful evaluation is always needed when prescribing NOACs.
Collapse
Affiliation(s)
- Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.,Multimedica IRCCS, Milan, Italy
| | - Nicola Ferri
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
| | - Marco Proietti
- Department of Clinical Sciences and Community Health, University of Milan, Via della Commenda 19, 20122, Milan, Italy. .,Geriatric Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. .,Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK.
| | - Giuseppe Boriani
- Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy
| |
Collapse
|
|
12
|
Bowman CM, Ma F, Mao J, Chen Y. Examination of Physiologically-Based Pharmacokinetic Models of Rosuvastatin. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2020; 10:5-17. [PMID: 33220025 PMCID: PMC7825190 DOI: 10.1002/psp4.12571] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/19/2020] [Indexed: 12/14/2022]
Abstract
Physiologically‐based pharmacokinetic (PBPK) modeling is increasingly used to predict drug disposition and drug–drug interactions (DDIs). However, accurately predicting the pharmacokinetics of transporter substrates and transporter‐mediated DDIs (tDDIs) is still challenging. Rosuvastatin is a commonly used substrate probe in DDI risk assessment for new molecular entities (NMEs) that are potential organic anion transporting polypeptide 1B or breast cancer resistance protein transporter inhibitors, and as such, several rosuvastatin PBPK models have been developed to try to predict the clinical DDI and support NME drug labeling. In this review, we examine five representative PBPK rosuvastatin models, discuss common challenges that the models have come across, and note remaining gaps. These shared learnings will help with the continuing efforts of rosuvastatin model validation, provide more information to understand transporter‐mediated drug disposition, and increase confidence in tDDI prediction.
Collapse
Affiliation(s)
- Christine M Bowman
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA
| | - Fang Ma
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA
| | - Jialin Mao
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA
| | - Yuan Chen
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA
| |
Collapse
|
|
13
|
Tomlinson B, Chan P, Zhang Y, Lam CWK. Efficacy and safety of add on therapies in patients with hypercholesterolemia undergoing statin therapy. Expert Opin Pharmacother 2020; 21:2137-2151. [PMID: 32772741 DOI: 10.1080/14656566.2020.1801638] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Statins are the first-line treatment to reduce cardiovascular (CV) events, mainly by reducing low-density-lipoprotein cholesterol (LDL-C), but many patients need additional treatments to reach the current lipid goals. AREAS COVERED Herein, the authors review the published literature on the efficacy and safety of the therapies that are most often added to statins to achieve lipid targets. EXPERT OPINION Ezetimibe is usually the first additional treatment to achieve LDL-C targets. It reduces LDL-C by about a further 20% and has an excellent safety and tolerability profile. The monoclonal antibody proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab, and alirocumab, can reduce LDL-C by ≥50% when added to statins and they also have a well-established safety and tolerability record. The recently approved bempedoic acid is well tolerated and appears to be free of skeletal muscle-related problems, but the CV outcome study with this drug has not been completed. Inclisiran, a small-interfering RNA targeting PCSK9 is at an advanced stage of development and the available data indicate a satisfactory safety profile and LDL-C lowering efficacy similar to the PCSK9 monoclonal antibodies with the advantage of less frequent administration.
Collapse
Affiliation(s)
- Brian Tomlinson
- Faculty of Medicine, Macau University of Science and Technology , Macau, China
| | - Paul Chan
- Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University , Taipei City, Taiwan
| | - Yuzhen Zhang
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine , Shanghai, China
| | | |
Collapse
|
|
14
|
Tomlinson B, Chan P, Zhang Y, Liu Z, Lam CWK. Pharmacokinetics of current and emerging treatments for hypercholesterolemia. Expert Opin Drug Metab Toxicol 2020; 16:371-385. [PMID: 32223657 DOI: 10.1080/17425255.2020.1749261] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Reduction of low-density-lipoprotein cholesterol (LDL-C) and other apolipoprotein B (apoB)-containing lipoproteins reduces cardiovascular (CV) events and greater reductions have greater benefits. Current lipid treatments cannot always achieve desirable LDL-C targets and additional or alternative treatments are often needed.Areas covered: In this article, we review the pharmacokinetics of the available and emerging treatments for hypercholesterolemia and focus on recently approved drugs and those at a late stage of development.Expert opinion: Statin pharmacokinetics are well known and appropriate drugs and doses can usually be chosen for individual patients to achieve LDL-C targets and avoid adverse effects and drug-drug interactions. Ezetimibe, icosapent ethyl and the monoclonal antibodies evolocumab and alirocumab have established efficacy and safety. Newer oral agents including pemafibrate and bempedoic acid have generally favorable pharmacokinetics supporting use in a wide range of patients. RNA-based therapies with antisense oligonucleotides are highly specific for their targets and those inhibiting apoB, apoCIII, angiopoietin-like protein 3 and lipoprotein(a) have shown promising results. The small-interfering RNA inclisiran has the notable advantage that a single subcutaneous administration may be effective for up to 6 months. The CV outcome trial results and long term safety data are eagerly awaited for these new agents.
Collapse
Affiliation(s)
- Brian Tomlinson
- Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Paul Chan
- Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan.,Research Center for Translational Medicine, Shanghai East Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Yuzhen Zhang
- Research Center for Translational Medicine, Shanghai East Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Zhongmin Liu
- Research Center for Translational Medicine, Shanghai East Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | | |
Collapse
|
|
15
|
Lorenzatti AJ, Toth PP. New Perspectives on Atherogenic Dyslipidaemia and Cardiovascular Disease. Eur Cardiol 2020; 15:1-9. [PMID: 32180834 PMCID: PMC7066832 DOI: 10.15420/ecr.2019.06] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/27/2019] [Indexed: 12/12/2022] Open
Abstract
Over the past few decades, atherogenic dyslipidaemia has become one of the most common phenotypic presentations of lipid abnormalities, being strongly and unequivocally associated with an increased risk of cardiovascular (CV) disease. Despite the excellent results achieved from statin and non-statin management of LDL cholesterol and CV events prevention, there still remains a significant residual risk, associated with the prevalence of non-LDL cholesterol lipid patterns characterised by elevated triglyceride levels, low HDL cholesterol, a preponderance of small and dense LDL particles, accumulation of remnant lipoproteins and postprandial hyperlipidaemia. These qualitative and quantitative lipid modifications are largely associated with insulin resistance, type 2 diabetes and obesity, the prevalence of which has grown to epidemic proportions throughout the world. In this review, we analyse the pathophysiology of this particular dyslipidaemia, its relationship with the development of atherosclerotic CV disease and, finally, briefly describe the therapeutic approaches, including changes in lifestyle and current pharmacological interventions to manage these lipid alterations aimed at preventing CV events.
Collapse
Affiliation(s)
- Alberto J Lorenzatti
- DAMIC Medical Institute, Rusculleda Foundation for Research, Cordoba, Argentina.,Department of Cardiology, Cordoba Hospital, Cordoba, Argentina
| | - Peter P Toth
- CGH Medical Center, Sterling, IL, US.,Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, US
| |
Collapse
|
|
16
|
Influence of OATP1B1 and BCRP polymorphisms on the pharmacokinetics and pharmacodynamics of rosuvastatin in elderly and young Korean subjects. Sci Rep 2019; 9:19410. [PMID: 31857620 PMCID: PMC6923423 DOI: 10.1038/s41598-019-55562-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 11/26/2019] [Indexed: 02/04/2023] Open
Abstract
A lack of information regarding whether genetic polymorphisms of SLCO1B1 and ABCG2 affect the pharmacokinetics (PKs)/pharmacodynamics (PDs) of rosuvastatin in elderly subjects prevents optimal individualized pharmacotherapy of rosuvastatin in clinical settings. This study aimed to investigate the effect of age and genetic polymorphisms and possible differences in genetic effects on the PKs/PDs of rosuvastatin between elderly and young subjects. Two separate clinical studies designed as open-label, one-sequence studies with multiple-dose administration for elderly (n = 20) and young (n = 32) subjects were conducted. All subjects received 20 mg of rosuvastatin once daily for 21 days. The exposure to rosuvastatin, characterized by the area under the time curve (AUC), increased by 23% in the elderly subjects compared with that of young subjects, which was not significant. When compared to the subjects with breast cancer resistance protein (BCRP) normal function, the exposure to rosuvastatin increased by 44% in young subjects (p = 0.0021) with BCRP intermediate function (IF) and by 35% and 59% (p > 0.05 for both) in elderly subjects with BCRP IF and low function, respectively. SLCO1B1 521T > C was also partially associated with a higher AUC of rosuvastatin in young subjects and a less pronounced increasing trend in elderly subjects (p > 0.05 for both). The lipid-lowering effect of rosuvastatin was less pronounced in the elderly subjects than in the young subjects, and genetic polymorphisms of neither SLCO1B1 nor ABCG2 significantly affected the PDs of rosuvastatin. The ABCG2 421C > A polymorphism was associated with the PKs of rosuvastatin and was identified as a more important determinant than the SLCO1B1 521T > C polymorphism in both elderly and young subjects.
Collapse
|
|
17
|
Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL, Goldstein LB, Chin C, Tannock LR, Miller M, Raghuveer G, Duell PB, Brinton EA, Pollak A, Braun LT, Welty FK. Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2019; 39:e38-e81. [PMID: 30580575 DOI: 10.1161/atv.0000000000000073] [Citation(s) in RCA: 446] [Impact Index Per Article: 74.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
One in 4 Americans >40 years of age takes a statin to reduce the risk of myocardial infarction, ischemic stroke, and other complications of atherosclerotic disease. The most effective statins produce a mean reduction in low-density lipoprotein cholesterol of 55% to 60% at the maximum dosage, and 6 of the 7 marketed statins are available in generic form, which makes them affordable for most patients. Primarily using data from randomized controlled trials, supplemented with observational data where necessary, this scientific statement provides a comprehensive review of statin safety and tolerability. The review covers the general patient population, as well as demographic subgroups, including the elderly, children, pregnant women, East Asians, and patients with specific conditions such as chronic disease of the kidney and liver, human immunodeficiency viral infection, and organ transplants. The risk of statin-induced serious muscle injury, including rhabdomyolysis, is <0.1%, and the risk of serious hepatotoxicity is ≈0.001%. The risk of statin-induced newly diagnosed diabetes mellitus is ≈0.2% per year of treatment, depending on the underlying risk of diabetes mellitus in the population studied. In patients with cerebrovascular disease, statins possibly increase the risk of hemorrhagic stroke; however, they clearly produce a greater reduction in the risk of atherothrombotic stroke and thus total stroke, as well as other cardiovascular events. There is no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis. In US clinical practices, roughly 10% of patients stop taking a statin because of subjective complaints, most commonly muscle symptoms without raised creatine kinase. In contrast, in randomized clinical trials, the difference in the incidence of muscle symptoms without significantly raised creatinine kinase in statin-treated compared with placebo-treated participants is <1%, and it is even smaller (0.1%) for patients who discontinued treatment because of such muscle symptoms. This suggests that muscle symptoms are usually not caused by pharmacological effects of the statin. Restarting statin therapy in these patients can be challenging, but it is important, especially in patients at high risk of cardiovascular events, for whom prevention of these events is a priority. Overall, in patients for whom statin treatment is recommended by current guidelines, the benefits greatly outweigh the risks.
Collapse
|
|
18
|
Mechanisms of simvastatin myotoxicity: The role of autophagy flux inhibition. Eur J Pharmacol 2019; 862:172616. [DOI: 10.1016/j.ejphar.2019.172616] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 08/14/2019] [Accepted: 08/16/2019] [Indexed: 12/19/2022]
|
|
19
|
Affiliation(s)
- D King
- Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
| | - M J Armstrong
- Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
| |
Collapse
|
|
20
|
Elam MB, Ginsberg HN, Lovato LC, Corson M, Largay J, Leiter LA, Lopez C, O'Connor PJ, Sweeney ME, Weiss D, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm R, Ismail-Beigi F, Goff DC, Fleg JL, Rosenberg Y, Byington RP. Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes. JAMA Cardiol 2019; 2:370-380. [PMID: 28030716 DOI: 10.1001/jamacardio.2016.4828] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Importance Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk. Objective To determine whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes. Design, Setting, and Participants Posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study between July 2009 and October 2014; 5 years of follow-up were completed for a total of 9.7 years at general community and academic outpatient research clinics in the United States and Canada. Of the original 5518 ACCORD Lipid Trial participants, 4644 surviving participants were selected based on the presence of type 2 diabetes and either prevalent CVD or CVD risk factors and high-density lipoprotein levels less than 50 mg/dL (<55 mg/dL for women and African American individuals). Interventions Passive follow-up of study participants previously treated with fenofibrate or masked placebo. Main Outcomes and Measures Occurrence of cardiovascular outcomes including primary composite outcome of fatal and nonfatal myocardial infarction and stroke in all participants and in prespecified subgroups. Results The 4644 follow-on study participants were broadly representative of the original ACCORD study population and included significant numbers of women (n = 1445; 31%), nonwhite individuals (n = 1094; 21%), and those with preexisting cardiovascular events (n = 1620; 35%). Only 4.3% of study participants continued treatment with fenofibrate following completion of ACCORD. High-density lipoprotein and triglyceride values rapidly equalized among participants originally randomized to fenofibrate or placebo. Over a median total postrandomization follow-up of 9.7 years, the hazard ratio (HR) for the primary study outcome among participants originally randomized to fenofibrate vs placebo (HR, 0.93; 95% CI, 0.83-1.05; P = .25) was comparable with that originally observed in ACCORD (HR, 0.92; 95% CI, 0.79-1,08; P = .32). Despite these overall neutral results, we continued to find evidence that fenofibrate therapy effectively reduced CVD in study participants with dyslipidemia, defined as triglyceride levels greater than 204 mg/dL and high-density lipoprotein cholesterol levels less than 34 mg/dL (HR, 0.73; 95% CI, 0.56-0.95). Conclusions and Relevance Extended follow-up of ACCORD-lipid trial participants confirms the original neutral effect of fenofibrate in the overall study cohort. The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol. A definitive trial of fibrate therapy in this patient population is needed to confirm these findings. Trial Registration clinicaltrials.gov Identifier: NCT00000620.
Collapse
Affiliation(s)
- Marshall B Elam
- Memphis Veterans Affairs Medical Center and University of Tennessee Health Sciences Center, Memphis
| | - Henry N Ginsberg
- Columbia University College of Physicians and Surgeons, New York, New York
| | - Laura C Lovato
- Wake Forest School of Medicine, Wake Forest, North Carolina
| | | | | | - Lawrence A Leiter
- Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Ontario, Canada
| | - Carlos Lopez
- Columbia University College of Physicians and Surgeons, New York, New York
| | | | | | - Daniel Weiss
- Diabetes Endocrine Nutrition Group, Mentor, Ohio
| | | | | | | | | | - Richard Grimm
- Berman Center for Outcomes and Clinical Research, Minneapolis, Minnesota
| | | | - David C Goff
- Colorado School of Public Health, Aurora, Colorado
| | - Jerome L Fleg
- National Heart, Lung, and Blood Institute, Division of Cardiovascular Sciences, Bethesda, Maryland
| | - Yves Rosenberg
- National Heart, Lung, and Blood Institute, Division of Cardiovascular Sciences, Bethesda, Maryland
| | | | | |
Collapse
|
|
21
|
Meech R, Hu DG, McKinnon RA, Mubarokah SN, Haines AZ, Nair PC, Rowland A, Mackenzie PI. The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms. Physiol Rev 2019; 99:1153-1222. [DOI: 10.1152/physrev.00058.2017] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to a broad range of lipophilic molecules. This biotransformation plays a critical role in elimination of a broad range of exogenous chemicals and by-products of endogenous metabolism, and also controls the levels and distribution of many endogenous signaling molecules. In mammals, the superfamily comprises four families: UGT1, UGT2, UGT3, and UGT8. UGT1 and UGT2 enzymes have important roles in pharmacology and toxicology including contributing to interindividual differences in drug disposition as well as to cancer risk. These UGTs are highly expressed in organs of detoxification (e.g., liver, kidney, intestine) and can be induced by pathways that sense demand for detoxification and for modulation of endobiotic signaling molecules. The functions of the UGT3 and UGT8 family enzymes have only been characterized relatively recently; these enzymes show different UDP-sugar preferences to that of UGT1 and UGT2 enzymes, and to date, their contributions to drug metabolism appear to be relatively minor. This review summarizes and provides critical analysis of the current state of research into all four families of UGT enzymes. Key areas discussed include the roles of UGTs in drug metabolism, cancer risk, and regulation of signaling, as well as the transcriptional and posttranscriptional control of UGT expression and function. The latter part of this review provides an in-depth analysis of the known and predicted functions of UGT3 and UGT8 enzymes, focused on their likely roles in modulation of levels of endogenous signaling pathways.
Collapse
Affiliation(s)
- Robyn Meech
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Dong Gui Hu
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Ross A. McKinnon
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Siti Nurul Mubarokah
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Alex Z. Haines
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Pramod C. Nair
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Andrew Rowland
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Peter I. Mackenzie
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| |
Collapse
|
|
22
|
Danielak D, Karaźniewicz-Łada M, Główka F. Assessment of the Risk of Rhabdomyolysis and Myopathy During Concomitant Treatment with Ticagrelor and Statins. Drugs 2019; 78:1105-1112. [PMID: 30003466 PMCID: PMC6061431 DOI: 10.1007/s40265-018-0947-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The introduction of ticagrelor, one of the first directly-acting oral antiplatelet drugs, provided new possibilities in the prevention of thrombotic events in patients with acute coronary syndromes (ACS). Current guidelines recommend ticagrelor in dual antiplatelet therapy with aspirin over clopidogrel for prevention of stent thrombosis in patients with ACS. Moreover, in the management of ACS, lipid-lowering treatment with high-intensity statin therapy is advised for secondary prevention of cardiovascular events over the long term. Despite the apparent advantages of combined antiplatelet and lipid-lowering treatments, a possible interaction between statins and ticagrelor may lead to myopathy and rhabdomyolysis. In this review, relevant information was gathered on the ticagrelor-statin interaction that might lead to this life-threatening condition. This review focuses on the most widely used statins—simvastatin, atorvastatin, and rosuvastatin. Possible mechanisms of this interaction are discussed, including CYP3A4 isoenzymes, organic anion transporter polypeptide (OATPs), P-glycoprotein and glucuronidation. PubMed database was searched for relevant case reports and all data gathered from the introduction of ticagrelor to March 2018 are presented and discussed. In summary, co-administration of statins and ticagrelor was found to be relatively safe in routinely prescribed doses. However, caution should be exercised, especially in elder populations.
Collapse
Affiliation(s)
- Dorota Danielak
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6 St, 60-781, Poznań, Poland.
| | - Marta Karaźniewicz-Łada
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6 St, 60-781, Poznań, Poland
| | - Franciszek Główka
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6 St, 60-781, Poznań, Poland
| |
Collapse
|
|
23
|
Cho PJ, Kim JH, Lee HS, Kim JA, Lee S. Identification of specific UGT1A9-mediated glucuronidation of licoricidin in human liver microsomes. Biopharm Drug Dispos 2019; 40:94-98. [DOI: 10.1002/bdd.2169] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 10/29/2018] [Accepted: 12/16/2018] [Indexed: 11/11/2022]
Affiliation(s)
- Pil Joung Cho
- BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences; Kyungpook National University; Daegu 41566 Republic of Korea
| | - Ju-Hyun Kim
- College of Pharmacy; Yeungnam University; Gyeongsan 38541 Republic of Korea
| | - Hye Suk Lee
- BK21 Plus Team for Creative Leader Program for Pharmacomics-based Future, Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy; The Catholic University of Korea; Bucheon 14662 Republic of Korea
| | - Jeong Ah Kim
- BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences; Kyungpook National University; Daegu 41566 Republic of Korea
| | - Sangkyu Lee
- BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences; Kyungpook National University; Daegu 41566 Republic of Korea
| |
Collapse
|
|
24
|
Hedrington MS, Davis SN. Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver. Expert Opin Drug Metab Toxicol 2018; 14:671-677. [PMID: 29847748 DOI: 10.1080/17425255.2018.1483337] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Drug-induced hepatic injury is the most common cause of acute liver failure in the United States. Peroxisome proliferator-activated receptor alpha (PPARα)-mediated drugs are included among the approximately 900 natural and synthetic substances, which have shown hepatotoxicity. Areas covered: This review will focus on fibrates - PPARα agonists and their implication in causing liver injury. Expert opinion: Compelling evidence for fibrate-induced hepatotoxicity is not available. Results have been varying because several large randomized clinical trials have reported similar elevations of plasma transaminase levels in fibrate or placebo treated groups. On the other hand, one meta-analysis has reported an increased risk of hepatotoxicity when fibrates are combined with statins. Fibrate induced clinically apparent liver damage has been demonstrated in case reports. However, there is a wide spectrum of clinical phenotypic presentations of these cases (onset of injury, pattern of enzyme elevation and resolution of the symptoms), which reduces the ability to identify specific cause and effect of any putative fibrate-induced hepatotoxicity. Thus, the current recommendations for using fibrates include monitoring of aminotransferase levels especially if combined with statins and discontinuation of the treatment only if the levels persist above three times the upper limit of normal.
Collapse
Affiliation(s)
- Maka S Hedrington
- a Department of Medicine , University of Maryland School of Medicine , Baltimore , Maryland , USA
| | - Stephen N Davis
- a Department of Medicine , University of Maryland School of Medicine , Baltimore , Maryland , USA
| |
Collapse
|
|
25
|
Dalugama C, Pathirage M, Kularatne SAM. Delayed presentation of severe rhabdomyolysis leading to acute kidney injury following atorvastatin-gemfibrozil combination therapy: a case report. J Med Case Rep 2018; 12:143. [PMID: 29784023 PMCID: PMC5963031 DOI: 10.1186/s13256-018-1685-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 04/09/2018] [Indexed: 12/28/2022] Open
Abstract
Background Rhabdomyolysis is a rare but serious complication of lipid-lowering therapy. Statin and fibrate combination increases the risk of rhabdomyolysis possibly by pharmacodynamic interactions. Advanced age, diabetes, hypothyroidism, polypharmacy, and renal impairment are known to increase the risk of rhabdomyolysis. Management strategies include fluid resuscitation and urine alkalinization. Renal indications such as refractory hyperkalemia, acidosis, fluid overload, or uremic complications mandate renal replacement therapy in rhabdomyolysis. Case presentation We report the case of a 62-year-old Sri Lankan Sinhalese man with dyslipidemia, type 2 diabetes mellitus with renal impairment, and hypothyroidism who was on atorvastatin; he was started on gemfibrozil and developed muscle symptoms. Although gemfibrozil was discontinued soon after, he presented with rhabdomyolysis with acute kidney injury 1 month later. He needed hemodialysis due to refractory hyperkalemia, metabolic acidosis, and fluid overload. Conclusions Rhabdomyolysis is a rare but serious complication due to lipid-lowering therapy with statins and fibrates. Treating physicians should be aware and patients should be warned to report about muscle symptoms after starting statins or fibrates. Rhabdomyolysis may occur with mild symptoms and signs and may occur later, even after discontinuation of the drug.
Collapse
Affiliation(s)
- Chamara Dalugama
- Department of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.
| | - Manoji Pathirage
- Department of Medicine, University of Peradeniya, Peradeniya, Sri Lanka
| | - S A M Kularatne
- Department of Medicine, University of Peradeniya, Peradeniya, Sri Lanka
| |
Collapse
|
|
26
|
Uchida M, Tajima Y, Kakuni M, Kageyama Y, Okada T, Sakurada E, Tateno C, Hayashi R. Organic Anion-Transporting Polypeptide (OATP)-Mediated Drug-Drug Interaction Study between Rosuvastatin and Cyclosporine A in Chimeric Mice with Humanized Liver. Drug Metab Dispos 2018; 46:11-19. [PMID: 29051147 DOI: 10.1124/dmd.117.075994] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 10/13/2017] [Indexed: 02/13/2025] Open
Abstract
The influence of transporters on the pharmacokinetics of drugs is being increasingly recognized, and DDIs via transporters may be a risk factor for adverse events. Cyclosporine A, a strong OATP inhibitor, has been reported to increase the systemic exposure of rosuvastatin, an OATP substrate, by 7.1-fold in clinical studies. PXB mice are chimeric mice with humanized livers that are highly repopulated with human hepatocytes and have been widely used for drug discovery in drug metabolism and pharmacokinetics studies. In the present study, we examined in vivo and in vitro DDIs between rosuvastatin and cyclosporine A in PXB mice and fresh human hepatocytes (PXB cells) obtained from PXB mice. We initially investigated the active transport of rosuvastatin into PXB cells, and found concentration-dependent uptake with a Michaelis-Menten constant value of 4.0 μmol/l and a Vmax value of 4.63 pmol/min per 106 cells. Cyclosporine A inhibited the uptake of rosuvastatin with an IC50 value of 0.21 μmol/l. We then examined in vivo DDIs, and the exposure of orally administered rosuvastatin increased by 3.3-fold and 11-fold in PXB mice pretreated with 10 and 50 mg/kg cyclosporine A, whereas it increased by 2.5-fold and 6.2-fold when rosuvastatin was administered intravenously, in studies that were conducted for considering gastrointestinal DDIs. The liver-to-blood concentration ratio of rosuvastatin was dose-dependently decreased by pretreatment with cyclosporine A in PXB mice and SCID mice. Observed DDIs in vivo were considered to be reasonable based on the estimated concentrations of cyclosporine A at the inlet to the liver and in the liver tissues of both mice. In conclusion, our results indicate that PXB mice might be a useful tool for predicting human OATP-mediated DDIs in drug discovery, and its limitation due to the differences of gastrointestinal condition from human should also be considered.
Collapse
Affiliation(s)
- Masashi Uchida
- Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan (M.U., Y.T., E.S., R.H.); and PhoenixBio Co., Ltd., Higashihiroshima, Hiroshima, Japan (M.K., Y.K., T.O., C.T.)
| | - Yoriko Tajima
- Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan (M.U., Y.T., E.S., R.H.); and PhoenixBio Co., Ltd., Higashihiroshima, Hiroshima, Japan (M.K., Y.K., T.O., C.T.)
| | - Masakazu Kakuni
- Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan (M.U., Y.T., E.S., R.H.); and PhoenixBio Co., Ltd., Higashihiroshima, Hiroshima, Japan (M.K., Y.K., T.O., C.T.)
| | - Yutaka Kageyama
- Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan (M.U., Y.T., E.S., R.H.); and PhoenixBio Co., Ltd., Higashihiroshima, Hiroshima, Japan (M.K., Y.K., T.O., C.T.)
| | - Taro Okada
- Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan (M.U., Y.T., E.S., R.H.); and PhoenixBio Co., Ltd., Higashihiroshima, Hiroshima, Japan (M.K., Y.K., T.O., C.T.)
| | - Eri Sakurada
- Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan (M.U., Y.T., E.S., R.H.); and PhoenixBio Co., Ltd., Higashihiroshima, Hiroshima, Japan (M.K., Y.K., T.O., C.T.)
| | - Chise Tateno
- Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan (M.U., Y.T., E.S., R.H.); and PhoenixBio Co., Ltd., Higashihiroshima, Hiroshima, Japan (M.K., Y.K., T.O., C.T.)
| | - Ryoji Hayashi
- Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan (M.U., Y.T., E.S., R.H.); and PhoenixBio Co., Ltd., Higashihiroshima, Hiroshima, Japan (M.K., Y.K., T.O., C.T.)
| |
Collapse
|
|
27
|
Kim CH, An H, Kim SH, Shin D. Pharmacokinetic and pharmacodynamic interaction between ezetimibe and rosuvastatin in healthy male subjects. DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:3461-3469. [PMID: 29255347 PMCID: PMC5723108 DOI: 10.2147/dddt.s146863] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Background and objective Rosuvastatin and ezetimibe are commonly applied in lipid-lowering pharmacotherapy. However, the pharmacokinetic (PK) interaction was not clear by the coadministration of rosuvastatin and ezetimibe. This study investigated the pharmacodynamic (PD) and PK interactions between rosuvastatin and ezetimibe through a crossover clinical trial. Subjects and methods A randomized, open-label, multiple-dose, two-treatment, two-period, two-sequence crossover study with two treatment parts was conducted in healthy male subjects. Study part A involved rosuvastatin, and study part B involved ezetimibe. A total of 25 subjects in both parts completed the PK and PD evaluations. Rosuvastatin (20 mg) or ezetimibe (10 mg) was administered once daily for 7 days as monotherapy or co-therapy. The plasma concentrations of rosuvastatin, total ezetimibe and free ezetimibe were measured for 72 h after day 7. Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) were investigated for the PD assessments on day 1 (pretreatment) and day 8. Results Rosuvastatin and ezetimibe presented multiple peaks. The 90% confidence intervals (CIs) of the geometric mean ratios for the peak plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve during the dosing interval at steady state (AUCτ,ss) of rosuvastatin and total ezetimibe were within the range 0.8-1.25. However, the coadministration increased the systemic exposure of free ezetimibe. In the PD assessments, rosuvastatin and ezetimibe monotherapy reduced the LDL-C and TC levels effectively. In addition, the lipid-lowering effects of the coadministration corresponded to an approximate summation of the effects of rosuvastatin and ezetimibe monotherapy. However, no significant changes in HDL-C were observed with rosuvastatin or ezetimibe treatment. No significant safety issue was noted. Conclusion The coadministration of rosuvastatin and ezetimibe revealed a bioequivalent PK interaction. Additional lipid-lowering effects, including decreased LDL-C and TC, were observed as expected in combination therapy without significant safety concern.
Collapse
Affiliation(s)
- Chang Hee Kim
- Department of Urology, Gachon University Gil Medical Center, Incheon
| | - Hyungmi An
- Department of Statistics, Seoul National University, Seoul
| | - Sung Hye Kim
- Clinical Development, Navipharm Co., Ltd., Suwon
| | - Dongseong Shin
- Clinical Trials Center, Gachon University Gil Medical Center, Incheon, South Korea
| |
Collapse
|
|
28
|
Association of miR-145 With Statin-Induced Skeletal Muscle Toxicity in Human Rhabdomyosarcoma RD Cells. J Pharm Sci 2017; 106:2873-2880. [DOI: 10.1016/j.xphs.2017.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/30/2017] [Accepted: 04/07/2017] [Indexed: 12/15/2022]
|
|
29
|
Practical recommendations for the management of cardiovascular risk associated with atherogenic dyslipidemia, with special attention to residual risk. Spanish adaptation of a European Consensus of Experts. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2017; 29:168-177. [PMID: 28433209 DOI: 10.1016/j.arteri.2016.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 12/03/2016] [Indexed: 11/26/2022]
Abstract
This document has discussed clinical approaches to managing cardiovascular risk in clinical practice, with special focus on residual cardiovascular risk associated with lipid abnormalities, especially atherogenic dyslipidaemia (AD). A simplified definition of AD was proposed to enhance understanding of this condition, its prevalence and its impact on cardiovascular risk. AD can be defined by high fasting triglyceride levels (≥2.3mmol/L / ≥200mg/dL) and low high-density lipoprotein cholesterol (HDL-c) levels (≤1,0 / 40 and ≤1,3mmol/L / 50mg/dL in men and women, respectively) in statin-treated patients at high cardiovascular risk. The use of a single marker for the diagnosis and treatment of AD, such as non-HDL-c, was advocated. Interventions including lifestyle optimization and low density lipoprotein (LDL) lowering therapy with statins (±ezetimibe) are recommended by experts. Treatment of residual AD can be performed with the addition of fenofibrate, since it can improve the complete lipoprotein profile and reduce the risk of cardiovascular events in patients with AD. Others clinical condictions in which fenofibrate may be prescribed include patients with very high TGs (≥5.6mmol/L / 500mg/dL), patients who are intolerant or resistant to statins, and patients with AD and at high cardiovascular risk. The fenofibrate-statin combination was considered by the experts to benefit from a favorable benefit-risk profile. In conclusion, cardiovascular experts adopt a multifaceted approach to the prevention of atherosclerotic cardiovascular disease, with lifestyle optimization, LDL-lowering therapy and treatment of AD with fenofibrate routinely used to help reduce a patient's overall cardiovascular risk.
Collapse
|
|
30
|
Herranz-López M, Borrás-Linares I, Olivares-Vicente M, Gálvez J, Segura-Carretero A, Micol V. Correlation between the cellular metabolism of quercetin and its glucuronide metabolite and oxidative stress in hypertrophied 3T3-L1 adipocytes. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2017; 25:25-28. [PMID: 28190467 DOI: 10.1016/j.phymed.2016.12.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/14/2016] [Accepted: 12/15/2016] [Indexed: 06/06/2023]
Abstract
BACKGROUND Quercetin (Q) is one of the most abundant flavonoids in human dietary sources and has been related to the capacity to ameliorate obesity-related pathologies. Quercetin-3-O-β-d-glucuronide (Q3GA) is supposed to be the main metabolite in blood circulation, but the intracellular final effectors for its activity are still unknown. HYPOTHESIS/PURPOSE To identify and quantitate the intracellular metabolites in hypertrophied adipocytes incubated with Q or Q3GA and to correlate them with the intracellular generation of oxygen radical species (ROS). METHODS Cytoplasmic fractions were obtained and quercetin metabolites were determined by liquid chromatography coupled to a time-of-flight mass detector with electrospray ionization (HPLC-DAD-ESI-TOF). Intracellular ROS generation was measured by a ROS-sensitive fluorescent probe. RESULTS Both Q and Q3GA were absorbed by hypertrophied adipocytes and metabolized to some extent to Q3GA and Q, respectively, but Q absorption was more efficient (1.92 ± 0.03µg/µg protein) and faster than that of Q3GA (0.12 ± 0.0015µg/µg protein), leading to a higher intracellular concentration of the aglycone. Intracellular decrease of ROS correlated with the presence of the most abundant quercetin metabolite. CONCLUSION Q and Q3GA are efficiently absorbed by hypertrophied adipocytes and metabolized to some extent to Q3GA and Q, respectively. The intracellular decrease of ROS in a hypertrophied adipocyte model treated with Q or Q3GA is correlated with the most abundant intracellular metabolite for the first time. Both compounds might be able to reach other intracellular targets, thus contributing to their bioactivity.
Collapse
Affiliation(s)
- María Herranz-López
- Institute of Molecular and Cell Biology (IMCB), Miguel Hernández University (UMH), Elche 03202, Alicante, Spain.
| | - Isabel Borrás-Linares
- Center for Research and Development of Functional Food (CIDAF), Science Technology Park Health, Armilla, Granada, Spain
| | - Mariló Olivares-Vicente
- Institute of Molecular and Cell Biology (IMCB), Miguel Hernández University (UMH), Elche 03202, Alicante, Spain
| | - Julio Gálvez
- CIBER-EHD, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Avenida del Conocimiento s/n 18016, Armilla, Granada, Spain
| | - Antonio Segura-Carretero
- Center for Research and Development of Functional Food (CIDAF), Science Technology Park Health, Armilla, Granada, Spain
| | - Vicente Micol
- Institute of Molecular and Cell Biology (IMCB), Miguel Hernández University (UMH), Elche 03202, Alicante, Spain; CIBER, Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud Carlos III (CB12/03/30038), Spain.
| |
Collapse
|
|
31
|
Wu BJ, Wu SYS, Chen CH, Hsiao YF, Huang CS, Liu WS. Effect of Genetic Polymorphisms in Detoxification Proteins on Treatment Outcome of Atorvastatin. INT J PHARMACOL 2017. [DOI: 10.3923/ijp.2017.198.204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
|
32
|
Siriangkhawut M, Tansakul P, Uchaipichat V. Prevalence of potential drug interactions in Thai patients receiving simvastatin: The causality assessment of musculoskeletal adverse events induced by statin interaction. Saudi Pharm J 2016; 25:823-829. [PMID: 28951665 PMCID: PMC5605837 DOI: 10.1016/j.jsps.2016.12.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 11/11/2016] [Accepted: 12/11/2016] [Indexed: 02/02/2023] Open
Abstract
Drug-drug interactions are one of the major risk factors associated with statin-induced myopathy. Although simvastatin is widely used in Thailand, studies investigating the prevalence of potential simvastatin-drug interactions (SDIs) and its clinical relevance in Thai population are still limited. We aimed to investigate the prevalence of potential SDIs (phase 1 study) and musculoskeletal adverse effects (AEs) associated with those interactions (phase 2 study). A phase 1 study was retrospectively conducted with outpatients at a 60-bed hospital who received simvastatin between July 1, 2012 and June 30, 2013. In phase 2, study was cross-sectionally conducted in outpatients whose prescriptions contain potential SDIs. Musculoskeletal AEs were evaluated by using symptom checklist questionnaires and measuring plasma creatinine kinase (CK). The causal relationship between the AEs and the potential SDIs was assessed using a Drug Interaction Probability Scale. Out of 3447 simvastatin users, potential SDIs were found in 314 patients (9.1%). The prevalence of prescriptions containing potential SDIs was in the range of 4.7–6.0%. Two-thirds of the potential SDIs were rated to be highly significant while more than 70% were in contraindication list. The most common precipitant drugs were gemfibrozil (382 prescriptions), colchicine (171 prescriptions) and amlodipine (152 prescriptions). Of 49 patients recruited into phase 2 study, we found that 31 patients (63.3%) had myopathy. Myalgia was the most frequently identified AEs (n = 18, 58.1%), followed by asymptomatic rising CK (n = 8, 25.8%), and myositis (n = 5, 16.1%). Musculoskeletal AEs associated with SDIs were found in 16 patients (51.6%). Of these, we found 50.0%, 31.3% and 18.8% had asymptomatic rising CK, myalgia, and myositis, respectively. Precipitant drugs associated with myopathy were amlodipine (2 possible cases), colchicine (3 possible cases), gemfibrozil (8 possible and 1 probable cases), nevirapine (1 possible case), and nicotinic acid (1 possible case). Potential SDIs have been found in the Thai population with a prevalence that is consistent with previous reports. Half of the musculoskeletal AEs identified were associated with SDIs. Systematic screening and management with interdisciplinary co-operation are needed to increase awareness of potential SDIs.
Collapse
Affiliation(s)
- Methira Siriangkhawut
- Piboonmungsaharn Hospital, Ubonratchathanee, Thailand
- Division of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | | | - Verawan Uchaipichat
- Division of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand
- Corresponding author at: Division of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand. Fax: +66 43202379.Division of Pharmacy PracticeFaculty of Pharmaceutical SciencesKhon Kaen UniversityKhon Kaen40002Thailand
| |
Collapse
|
|
33
|
Papademetriou V, Lovato L, Tsioufis C, Cushman W, Applegate WB, Mottle A, Punthakee Z, Nylen E, Doumas M. Effects of High Density Lipoprotein Raising Therapies on Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus, with or without Renal Impairment: The Action to Control Cardiovascular Risk in Diabetes Study. Am J Nephrol 2016; 45:136-145. [PMID: 27992863 DOI: 10.1159/000453626] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 11/14/2016] [Indexed: 11/19/2022]
Abstract
BACKGROUND The role of high density lipoprotein-raising interventions in addition to statin therapy in patients with diabetes remains controversial. Chronic kidney disease (CKD) is a strong modifier of cardiovascular (CV) outcomes. We therefore investigated the impact of CKD status at baseline on outcomes in patients with diabetes randomized to standard statin or statin plus fenofibrate treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial. METHODS Among 5,464 participants in the ACCORD lipid trial, 3,554 (65%) were free of CKD at baseline, while 1,910 (35%) had mild to moderate CKD. Differences in CV outcomes during follow-up between CKD and non-CKD subgroups were examined. In addition, the effect of fenofibrate as compared to placebo on CV outcomes was examined for both subgroups. RESULTS All CV outcomes were 1.4-3 times higher among patients with CKD as compared to non-CKD patients. In patients with CKD, the addition of fenofibrate had no effect on any of the primary or secondary outcomes. In patients without CKD, however, the addition of fenofibrate was associated with a significant 36% reduction of CV mortality (hazards ratio [HR] 0.64; 95% CI 0.42-0.97; p value for treatment interaction <0.05) and 44% lower rate of fatal or non-fatal congestive heart failure (CHF; HR 0.56; 95% CI 0.37-0.84; p value treatment interaction <0.03). CONCLUSIONS For patients with type 2 diabetes at high CV risk but no CKD, fenofibrate therapy added to statin reduced the CV mortality and the rate of fatal and non-fatal CHF.
Collapse
|
|
34
|
Wiggins BS, Saseen JJ, Page RL, Reed BN, Sneed K, Kostis JB, Lanfear D, Virani S, Morris PB. Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation 2016; 134:e468-e495. [DOI: 10.1161/cir.0000000000000456] [Citation(s) in RCA: 156] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
|
|
35
|
Tornio A, Neuvonen PJ, Niemi M, Backman JT. Role of gemfibrozil as an inhibitor of CYP2C8 and membrane transporters. Expert Opin Drug Metab Toxicol 2016; 13:83-95. [PMID: 27548563 DOI: 10.1080/17425255.2016.1227791] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Cytochrome P450 (CYP) 2C8 is a drug metabolizing enzyme of major importance. The lipid-lowering drug gemfibrozil has been identified as a strong inhibitor of CYP2C8 in vivo. This effect is due to mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-β-glucuronide. In vivo, gemfibrozil is a fairly selective CYP2C8 inhibitor, which lacks significant inhibitory effect on other CYP enzymes. Gemfibrozil can, however, have a smaller but clinically meaningful inhibitory effect on membrane transporters, such as organic anion transporting polypeptide 1B1 and organic anion transporter 3. Areas covered: This review describes the inhibitory effects of gemfibrozil on CYP enzymes and membrane transporters. The clinical drug interactions caused by gemfibrozil and the different mechanisms contributing to the interactions are reviewed in detail. Expert opinion: Gemfibrozil is a useful probe inhibitor of CYP2C8 in vivo, but its effect on membrane transporters has to be taken into account in study design and interpretation. Moreover, gemfibrozil could be used to boost the pharmacokinetics of CYP2C8 substrate drugs. Identification of gemfibrozil 1-O-β-glucuronide as a potent mechanism-based inhibitor of CYP2C8 has led to recognition of glucuronide metabolites as perpetrators of drug-drug interactions. Recently, also acyl glucuronide metabolites of clopidogrel and deleobuvir have been shown to strongly inhibit CYP2C8.
Collapse
Affiliation(s)
- Aleksi Tornio
- a Department of Clinical Pharmacology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland
| | - Pertti J Neuvonen
- a Department of Clinical Pharmacology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland
| | - Mikko Niemi
- a Department of Clinical Pharmacology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland
| | - Janne T Backman
- a Department of Clinical Pharmacology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland
| |
Collapse
|
|
36
|
[Part I. Fibrates in primary and secondary prevention]. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ARTERIOSCLEROSIS 2016; 28 Suppl 3:3-10. [PMID: 27473465 DOI: 10.1016/s0214-9168(16)30083-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
|
|
37
|
Kunze A, Poller B, Huwyler J, Camenisch G. Application of the extended clearance concept classification system (ECCCS) to predict the victim drug-drug interaction potential of statins. Drug Metab Pers Ther 2016; 30:175-88. [PMID: 25996489 DOI: 10.1515/dmdi-2015-0003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 04/08/2015] [Indexed: 02/05/2023]
Abstract
BACKGROUND During drug development, it is an important safety factor to identify the potential of new molecular entities to become a victim of drug-drug interactions (DDIs). In preclinical development, however, anticipation of clinical DDIs remains challenging due to the lack of in vivo human pharmacokinetic data. METHODS We applied a recently developed in vitro-in vivo extrapolation method, including hepatic metabolism and transport processes, herein referred to as the Extended Clearance Concept Classification System (ECCCS). The human hepatic clearances and the victim DDI potentials were predicted for atorvastatin, cerivastatin, fluvastatin, lovastatin acid, pitavastatin, pravastatin, rosuvastatin, and simvastatin acid. RESULTS Hepatic statin clearances were well-predicted by the ECCCS with six out of eight clearances projected within a two-fold deviation to reported values. In addition, worst-case DDI predictions were projected for each statin. Based on the ECCCS class assignment (4 classes), the mechanistic interplay of metabolic and transport processes, resulting in different DDI risks, was well-reflected by our model. Furthermore, predictions of clinically observed statins DDIs in combination with relevant perpetrator drugs showed good quantitative correlations with clinical observations. CONCLUSIONS The ECCCS represents a powerful tool to anticipate the DDI potential of victim drugs based on in vitro drug metabolism and transport data.
Collapse
|
|
38
|
Ferrari R, Aguiar C, Alegria E, Bonadonna RC, Cosentino F, Elisaf M, Farnier M, Ferrières J, Filardi PP, Hancu N, Kayikcioglu M, Mello e Silva A, Millan J, Reiner Ž, Tokgozoglu L, Valensi P, Viigimaa M, Vrablik M, Zambon A, Zamorano JL, Catapano AL. Current practice in identifying and treating cardiovascular risk, with a focus on residual risk associated with atherogenic dyslipidaemia. Eur Heart J Suppl 2016; 18:C2-C12. [DOI: 10.1093/eurheartj/suw009] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
|
|
39
|
Badri PS, King JR, Polepally AR, McGovern BH, Dutta S, Menon RM. Dosing Recommendations for Concomitant Medications During 3D Anti-HCV Therapy. Clin Pharmacokinet 2016; 55:275-95. [PMID: 26330025 PMCID: PMC4761011 DOI: 10.1007/s40262-015-0317-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The development of direct-acting antiviral (DAA) agents has reinvigorated the treatment of hepatitis C virus infection. The availability of multiple DAA agents and drug combinations has enabled the transition to interferon-free therapy that is applicable to a broad range of patients. However, these DAA combinations are not without drug-drug interactions (DDIs). As every possible DDI permutation cannot be evaluated in a clinical study, guidance is needed for healthcare providers to avoid or minimize drug interaction risk. In this review, we evaluated the DDI potential of the novel three-DAA combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir (the 3D regimen) with more than 200 drugs representing 19 therapeutic drug classes. Outcomes of these DDI studies were compared with the metabolism and elimination routes of prospective concomitant medications to develop mechanism-based and drug-specific guidance on interaction potential. This analysis revealed that the 3D regimen is compatible with many of the drugs that are commonly prescribed to patients with hepatitis C virus infection. Where interaction is possible, risk can be mitigated by paying careful attention to concomitant medications, adjusting drug dosage as needed, and monitoring patient response and/or clinical parameters.
Collapse
Affiliation(s)
- Prajakta S Badri
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA.
| | - Jennifer R King
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA
| | - Akshanth R Polepally
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA
| | - Barbara H McGovern
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA
| | - Sandeep Dutta
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA
| | - Rajeev M Menon
- Clinical Pharmacology and Pharmacometrics (R4PK), AbbVie, Inc., 1 North Waukegan Rd, AP13A-3, North Chicago, IL, 60064, USA
| |
Collapse
|
|
40
|
|
|
41
|
[Consensus for pharmacologic treatment of atherogenic dyslipidemia with statin-fenofibrate combined therapy]. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2016; 28:87-93. [PMID: 26811267 DOI: 10.1016/j.arteri.2015.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Indexed: 10/22/2022]
Abstract
LDLc levels are associated with increase of cardiovascular risk, and statins are currently used for their control. Nevertheless, a despite of LDLc levels at goal, a residual risk is persistent, commonly associated with persistent lipids modifications (high triglycerides and low HDLc). So, it is necessary to evaluate triglycerides and HDL to assessment cardiovascular risk. Clinical data are consistent with efficacy and safety of combination therapy with statin and other lipid lowering drugs, for instance fenofibrate. Patients with hipertriglyceridemia and low HDLc are the group with most potential improve. In that patients with atherogenic dyslipidemia, the target for therapeutic objectives related with non-HDL-cholesterol is a priority, because non-HDL-cholesterol is considered as a more accuracy measure to assessment cardiovascular risk.
Collapse
|
|
42
|
Backman JT, Filppula AM, Niemi M, Neuvonen PJ. Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev 2016; 68:168-241. [PMID: 26721703 DOI: 10.1124/pr.115.011411] [Citation(s) in RCA: 167] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
During the last 10-15 years, cytochrome P450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed in human liver and is known to metabolize more than 100 drugs. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is increasing. Similarly, many drugs have been identified as CYP2C8 inhibitors or inducers. In vivo, already a small dose of gemfibrozil, i.e., 10% of its therapeutic dose, is a strong, irreversible inhibitor of CYP2C8. Interestingly, recent findings indicate that the acyl-β-glucuronides of gemfibrozil and clopidogrel cause metabolism-dependent inactivation of CYP2C8, leading to a strong potential for drug interactions. Also several other glucuronide metabolites interact with CYP2C8 as substrates or inhibitors, suggesting that an interplay between CYP2C8 and glucuronides is common. Lack of fully selective and safe probe substrates, inhibitors, and inducers challenges execution and interpretation of drug-drug interaction studies in humans. Apart from drug-drug interactions, some CYP2C8 genetic variants are associated with altered CYP2C8 activity and exhibit significant interethnic frequency differences. Herein, we review the current knowledge on substrates, inhibitors, inducers, and pharmacogenetics of CYP2C8, as well as its role in clinically relevant drug interactions. In addition, implications for selection of CYP2C8 marker and perpetrator drugs to investigate CYP2C8-mediated drug metabolism and interactions in preclinical and clinical studies are discussed.
Collapse
Affiliation(s)
- Janne T Backman
- Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N., P.J.N.)
| | - Anne M Filppula
- Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N., P.J.N.)
| | - Mikko Niemi
- Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N., P.J.N.)
| | - Pertti J Neuvonen
- Department of Clinical Pharmacology, University of Helsinki (J.T.B., A.M.F., M.N., P.J.N.), and Helsinki University Hospital, Helsinki, Finland (J.T.B., M.N., P.J.N.)
| |
Collapse
|
|
43
|
Aguiar C, Alegria E, Bonadonna RC, Catapano AL, Cosentino F, Elisaf M, Farnier M, Ferrières J, Filardi PP, Hancu N, Kayikcioglu M, Mello e Silva A, Millan J, Reiner Ž, Tokgozoglu L, Valensi P, Viigimaa M, Vrablik M, Zambon A, Zamorano JL, Ferrari R. A review of the evidence on reducing macrovascular risk in patients with atherogenic dyslipidaemia: A report from an expert consensus meeting on the role of fenofibrate–statin combination therapy. ATHEROSCLEROSIS SUPP 2015; 19:1-12. [DOI: 10.1016/s1567-5688(15)30001-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
|
|
44
|
Abstract
Recent guidelines for treating patients with diabetes categorize the disorder as a coronary heart disease (CHD) equivalent and urge aggressive treatment of modifiable risk factors, such as plasma levels of low-density lipoprotein cholesterol (LDL-C). In this article, Dr Rosenson discusses the rationale for cholesterol lowering in patients with diabetes, the lipoprotein abnormalities that accompany insulin resistance, and the prognostic significance of high LDL particle numbers. He also highlights major findings from recent clinical trials to explore statin therapy and other treatment strategies for lowering lipoprotein levels in this patient population.
Collapse
|
|
45
|
Hirota T, Ieiri I. Drug-drug interactions that interfere with statin metabolism. Expert Opin Drug Metab Toxicol 2015; 11:1435-47. [PMID: 26058399 DOI: 10.1517/17425255.2015.1056149] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Lipid-lowering drugs, especially hydroxymethylglutaryl-CoA reductase inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic diseases. The benefits of statins are well documented. However, myotoxic side effects, which can sometimes be severe, including myopathy or rhabdomyolysis, have been associated with the use of statins. In some cases, this toxicity is associated with pharmacokinetic alterations. Potent inhibitors of CYP 3A4 significantly increase plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin. Fluvastatin is metabolized by CYP2C9, while pravastatin, rosuvastatin and pitavastatin are not susceptible to inhibition by any CYP. AREAS COVERED This review discusses the pharmacokinetic aspects of the drug-drug interaction with statins and genetic polymorphisms in CYPs, which are involved in the metabolism of statins, and highlights the importance of establishing a system utilizing electronic medical information practically to avoid adverse drug reactions. EXPERT OPINION An understanding of the mechanisms underlying statin interactions will help to minimize drug interactions and develop statins that are less prone to adverse interactions. Quantitatively analyzed information for the low-density lipoprotein cholesterol lowering effects of statin based on electronic medical records may be useful for avoiding the adverse effect of statins.
Collapse
Affiliation(s)
- Takeshi Hirota
- a Kyushu University, Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Department of Clinical Pharmacokinetics , Fukuoka 8128582, Japan +81 92 642 6657 ; +81 92 642 6660 ;
| | | |
Collapse
|
|
46
|
Prueksaritanont T, Chu X, Evers R, Klopfer SO, Caro L, Kothare PA, Dempsey C, Rasmussen S, Houle R, Chan G, Cai X, Valesky R, Fraser IP, Stoch SA. Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin. Br J Clin Pharmacol 2015; 78:587-98. [PMID: 24617605 DOI: 10.1111/bcp.12377] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 03/05/2014] [Indexed: 12/14/2022] Open
Abstract
AIMS Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion-transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters. METHODS The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems. RESULTS Rifampicin markedly increased exposures of both statins, with greater differential increases after PO vs. IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration-time curve were 5.7- and 7.6-fold for pitavastatin and 4.4- and 3.3-fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3. CONCLUSIONS The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.
Collapse
|
|
47
|
Oda S, Fukami T, Yokoi T, Nakajima M. A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab Pharmacokinet 2015; 30:30-51. [DOI: 10.1016/j.dmpk.2014.12.001] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 11/24/2014] [Accepted: 12/02/2014] [Indexed: 01/24/2023]
|
|
48
|
Hu DG, Meech R, McKinnon RA, Mackenzie PI. Transcriptional regulation of human UDP-glucuronosyltransferase genes. Drug Metab Rev 2014; 46:421-58. [PMID: 25336387 DOI: 10.3109/03602532.2014.973037] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Glucuronidation is an important metabolic pathway for many small endogenous and exogenous lipophilic compounds, including bilirubin, steroid hormones, bile acids, carcinogens and therapeutic drugs. Glucuronidation is primarily catalyzed by the UDP-glucuronosyltransferase (UGT) 1A and two subfamilies, including nine functional UGT1A enzymes (1A1, 1A3-1A10) and 10 functional UGT2 enzymes (2A1, 2A2, 2A3, 2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28). Most UGTs are expressed in the liver and this expression relates to the major role of hepatic glucuronidation in systemic clearance of toxic lipophilic compounds. Hepatic glucuronidation activity protects the body from chemical insults and governs the therapeutic efficacy of drugs that are inactivated by UGTs. UGT mRNAs have also been detected in over 20 extrahepatic tissues with a unique complement of UGT mRNAs seen in almost every tissue. This extrahepatic glucuronidation activity helps to maintain homeostasis and hence regulates biological activity of endogenous molecules that are primarily inactivated by UGTs. Deciphering the molecular mechanisms underlying tissue-specific UGT expression has been the subject of a large number of studies over the last two decades. These studies have shown that the constitutive and inducible expression of UGTs is primarily regulated by tissue-specific and ligand-activated transcription factors (TFs) via their binding to cis-regulatory elements (CREs) in UGT promoters and enhancers. This review first briefly summarizes published UGT gene transcriptional studies and the experimental models and tools utilized in these studies, and then describes in detail the TFs and their respective CREs that have been identified in the promoters and/or enhancers of individual UGT genes.
Collapse
Affiliation(s)
- Dong Gui Hu
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre , Bedford Park, SA , Australia
| | | | | | | |
Collapse
|
|
49
|
Moßhammer D, Schaeffeler E, Schwab M, Mörike K. Mechanisms and assessment of statin-related muscular adverse effects. Br J Clin Pharmacol 2014; 78:454-66. [PMID: 25069381 PMCID: PMC4243897 DOI: 10.1111/bcp.12360] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 02/14/2014] [Indexed: 12/11/2022] Open
Abstract
Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers.
Collapse
Affiliation(s)
- Dirk Moßhammer
- Division of General Practice, University Hospital TübingenTübingen, D-72074, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch Institute of Clinical PharmacologyStuttgart, D-70376, Germany
- University TübingenTübingen, Germany
| | - Matthias Schwab
- Department of Clinical Pharmacology, University Hospital TübingenTübingen, D-72076, Germany
- Dr. Margarete Fischer-Bosch Institute of Clinical PharmacologyStuttgart, D-70376, Germany
- University TübingenTübingen, Germany
| | - Klaus Mörike
- Department of Clinical Pharmacology, University Hospital TübingenTübingen, D-72076, Germany
| |
Collapse
|
|
50
|
Jamei M, Bajot F, Neuhoff S, Barter Z, Yang J, Rostami-Hodjegan A, Rowland-Yeo K. A mechanistic framework for in vitro-in vivo extrapolation of liver membrane transporters: prediction of drug-drug interaction between rosuvastatin and cyclosporine. Clin Pharmacokinet 2014; 53:73-87. [PMID: 23881596 PMCID: PMC3889821 DOI: 10.1007/s40262-013-0097-y] [Citation(s) in RCA: 122] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background and Objectives The interplay between liver metabolising enzymes and transporters is a complex process involving system-related parameters such as liver blood perfusion as well as drug attributes including protein and lipid binding, ionisation, relative magnitude of passive and active permeation. Metabolism- and/or transporter-mediated drug–drug interactions (mDDIs and tDDIs) add to the complexity of this interplay. Thus, gaining meaningful insight into the impact of each element on the disposition of a drug and accurately predicting drug–drug interactions becomes very challenging. To address this, an in vitro–in vivo extrapolation (IVIVE)-linked mechanistic physiologically based pharmacokinetic (PBPK) framework for modelling liver transporters and their interplay with liver metabolising enzymes has been developed and implemented within the Simcyp Simulator®. Methods In this article an IVIVE technique for liver transporters is described and a full-body PBPK model is developed. Passive and active (saturable) transport at both liver sinusoidal and canalicular membranes are accounted for and the impact of binding and ionisation processes is considered. The model also accommodates tDDIs involving inhibition of multiple transporters. Integrating prior in vitro information on the metabolism and transporter kinetics of rosuvastatin (organic-anion transporting polypeptides OATP1B1, OAT1B3 and OATP2B1, sodium-dependent taurocholate co-transporting polypeptide [NTCP] and breast cancer resistance protein [BCRP]) with one clinical dataset, the PBPK model was used to simulate the drug disposition of rosuvastatin for 11 reported studies that had not been used for development of the rosuvastatin model. Results The simulated area under the plasma concentration–time curve (AUC), maximum concentration (Cmax) and the time to reach Cmax (tmax) values of rosuvastatin over the dose range of 10–80 mg, were within 2-fold of the observed data. Subsequently, the validated model was used to investigate the impact of coadministration of cyclosporine (ciclosporin), an inhibitor of OATPs, BCRP and NTCP, on the exposure of rosuvastatin in healthy volunteers. Conclusion The results show the utility of the model to integrate a wide range of in vitro and in vivo data and simulate the outcome of clinical studies, with implications for their design. Electronic supplementary material The online version of this article (doi:10.1007/s40262-013-0097-y) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- M Jamei
- Simcyp Limited (A Certara Company), Blades Enterprise Centre, John Street, S2 4SU, Sheffield, UK,
| | | | | | | | | | | | | |
Collapse
|