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.

中文翻译：

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细胞色素P450 2C8在药物代谢和相互作用中的作用。

在过去的10-15年中，细胞色素P450（CYP）2C8已经成为一种重要的药物代谢酶。CYP2C8在人类肝脏中高表达，并且已知能代谢100多种药物。CYP2C8底物药物包括阿莫地喹，西立伐他汀，达沙布韦，enzalutamide，伊马替尼，洛哌丁胺，孟鲁司特，紫杉醇，吡格列酮，瑞格列奈和罗格列酮，并且数量正在增加。同样，许多药物已被确定为CYP2C8抑制剂或诱导剂。在体内，已经有少量的吉非贝齐（即其治疗剂量的10％）是一种强的，不可逆的CYP2C8抑制剂。有趣的是，最近的发现表明吉非贝齐和氯吡格雷的酰基-β-葡萄糖醛酸导致CYP2C8的代谢依赖性失活，从而导致药物相互作用的强大潜力。另外，其他几种葡糖醛酸苷代谢物也与CYP2C8相互作用作为底物或抑制剂，这表明CYP2C8和葡糖醛酸苷之间的相互作用很普遍。缺乏完全选择性和安全的探针底物，抑制剂和诱导剂，对人体中药物相互作用研究的执行和解释提出了挑战。除药物相互作用外，某些CYP2C8遗传变异与CYP2C8活性改变有关，并表现出显着的种族间频率差异。在本文中，我们综述了有关CYP2C8的底物，抑制剂，诱导剂和药物遗传学的最新知识，以及其在临床相关药物相互作用中的作用。此外，还讨论了在临床前和临床研究中选择CYP2C8标记物和犯罪者药物以研究CYP2C8介导的药物代谢和相互作用的意义。