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Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

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Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions 1521-0081/68/1/168–241$25.00 http://dx.doi.org/10.1124/pr.115.011411 PHARMACOLOGICAL REVIEWS Pharmacol Rev 68:168–241, January 2016 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: MARKKU KOULU Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions Janne T. Backman, Anne M. Filppula, Mikko Niemi, and 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.) Abstract ...................................................................................169 I. Introduction . ..............................................................................169 II. Basic Characteristics of Cytochrome P450 2C8 . ..........................................170 A. Genomic Organization and Transcriptional Regulation . ...............................170 B. Protein Structure ......................................................................171 C. Expression .............................................................................172 III. Substrates of Cytochrome P450 2C8. ......................................................173 A. Drugs..................................................................................173 1. Anticancer Agents...................................................................173 Downloaded from 2. Antidiabetic Agents. ................................................................183 3. Antimalarial Agents.................................................................183 4. Lipid-lowering Drugs. ............................................................184 5. Other Drugs. .......................................................................184 6. Glucuronide Metabolites.............................................................186 B. Endogenous and Natural Compounds. ................................................187 by guest on March 4, 2019 IV. Pharmacogenetics. ........................................................................187 A. Population Genetics . ..................................................................187 B. Functional Studies . ..................................................................191 C. Effects on Drug Metabolism in Humans ................................................192 V. In Vitro Inhibition and Induction of Cytochrome P450 2C8 . ...............................193 A. Reversible Inhibition . ..................................................................193 1. Drugs That Act as Inhibitors of Cytochrome P450 2C8. ..............................193 2. Natural Compounds. ................................................................210 B. Metabolism-dependent Inhibition . ......................................................210 C. Induction ..............................................................................210 VI. Clinical Drug Interactions Mediated via Cytochrome P450 2C8 .............................212 A. General Aspects........................................................................212 B. Gemfibrozil as Prototypical Inhibitor . ................................................214 1. In Vitro Versus In Vivo.. ............................................................214 2. Gemfibrozil Dose Versus CYP2C8 Inhibition. .....................................216 3. Onset and Duration of CYP2C8 Inhibition by Gemfibrozil. .........................216 4. Quantification of CYP2C8-Mediated Drug Interactions in Humans. ..................216 C. Inhibition-Mediated Drug Interactions and Their Clinical Significance ..................217 1. Repaglinide. ........................................................................217 2. Other Oral Antidiabetic Drugs.......................................................218 3. Amodiaquine. .......................................................................219 4. Statins..............................................................................219 5. Anticancer Drugs.. ..................................................................220 This work was supported by grants from the Academy of Finland [Grant decision 278123, 2014], the Helsinki University Central Hospital Research Fund, and the Sigrid Juselius Foundation (Helsinki, Finland). Address correspondence to: Prof. Janne T. Backman, Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, P.O. Box 705, FI-00029 HUS, Finland. E-mail: [email protected] dx.doi.org/10.1124/pr.115.011411. 168 Role of CYP2C8 in Drug Metabolism and Interactions 169 6. Antiviral Drugs. ..................................................................221 7. Antiasthmatic Drugs. ............................................................221 8. Other Substrate or Inhibitor Drugs. ................................................221 D. Induction-Mediated Drug Interactions . ................................................222 1. Rifampin (Rifampicin). ............................................................222 VII. Points to Consider When Investigating Cytochrome P450 2C8-Mediated Drug Metabolism and Interactions . ............................................................222 A. InVitro................................................................................222 1. General Aspects. ..................................................................222 2. Assessment of CYP2C8 Activity In Vitro. ..........................................223 3. In Vitro Methods to Estimate the Contribution of CYP2C8 in the Metabolism of a Drug. ........................................................................224 B. In Vivo . ..............................................................................224 1. General Aspects. ..................................................................224 2. In Vivo Cytochrome P450 2C8 Probe Substrates. ....................................226 3. In Vivo Cytochrome P450 2C8 Probe Inhibitors. .....................................226 VIII. Conclusions and Future Prospects..........................................................227 Acknowledgments. ........................................................................228 References . ..............................................................................228 Abstract——During the last 10-15 years, cytochrome glucuronide metabolites interact with CYP2C8 as P450 (CYP) 2C8 has emerged as an important drug- substrates or inhibitors, suggesting that an interplay metabolizing enzyme. CYP2C8 is highly expressed in between CYP2C8 and glucuronides is common. Lack of human liver and is known to metabolize more than 100 fully selective and safe probe substrates, inhibitors, drugs. CYP2C8 substrate drugs include amodiaquine, and inducers challenges execution and interpretation cerivastatin, dasabuvir, enzalutamide, imatinib, of drug-drug interaction studies in humans. Apart from loperamide, montelukast, paclitaxel, pioglitazone, drug-drug interactions, some CYP2C8 genetic variants repaglinide, and rosiglitazone, and the number is are associated with altered CYP2C8 activity and exhibit increasing. Similarly, many drugs have been identified significant interethnic frequency differences. Herein, as CYP2C8 inhibitors or inducers. In vivo, already a small we review the current knowledge on substrates, inhibitors, dose of gemfibrozil, i.e., 10% of its therapeutic dose, is a inducers, and pharmacogenetics of CYP2C8, as well as strong, irreversible inhibitor of CYP2C8. Interestingly, its role in clinically relevant drug interactions. In recent findings indicate that the acyl-b-glucuronides addition, implications for selection of CYP2C8 marker of gemfibrozil and clopidogrel cause metabolism- and perpetrator drugs to investigate CYP2C8-mediated dependent inactivation of CYP2C8, leading to a strong drug metabolism and interactions in preclinical and potential for drug interactions. Also several other clinical studies are discussed. I. Introduction (HMG-CoA) reductase inhibitor cerivastatin, a CYP2C8 substrate, resulting in rhabdomyolysis cases and fatalities Cytochrome P450 (CYP) 2C8 accounts for approxi- mately 6–7% of the total hepatic CYP content (Rowland brought attention to the importance of CYP2C8 in drug Yeoetal.,2004;Inoueetal.,2006; Rostami-Hodjegan and metabolism (Backman et al., 2002; Staffa et al., 2002; Tucker, 2007; Achour et al., 2014). The importance of Wang et al., 2002; Chang et al., 2004; Huang et al., 2008). CYP2C8 causing variation in drug response via drug-drug The event was the onset of a broadening scientific in- interactions and pharmacogenetic polymorphisms has terestinCYP2C8,promptlyconvincingdrugregulatory been recognized only for the last 10–15 years. In the authorities to acknowledge CYP2C8 as one of the major beginning of the millennium, the pharmacokinetic drug- drug-metabolizing CYP enzymes. drug interaction between the fibric acid derivative gemfi- Drugs that were introduced into clinical use before brozil and the 3-hydroxy-3-methylglutaryl-coenzyme A the role of CYP2C8 was recognized may have deficient ABBREVIATIONS: AUC, area under the plasma concentration-time curve; C/EBPa, CCAAT/enhancer-binding protein a; CAR, constitutive androstane receptor; CITCO, [6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime; CLint, intrinsic clearance; Cmax, peak concentration; CYP, cytochrome P450; EMA, European Medicines Agency; FDA, Food and Drug Administration; GR, glucocorticoid receptor; HLM, human
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