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Clinical Drugs Undergoing Polymorphic Metabolism by Human Cytochrome P450 2C9 and the Implication in Drug Development

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Abstract:

CYP2C9 metabolizes more than 100 clinically used drugs including phenytoin, S-warfarin, tolbutamide, glipizide, diclofenac, and losartan with varying contributions. CYP2C9 is considered one of the most important CYPs, with substrate specificity typical of many new chemical entities (i.e. lipophilic bases). A large interindividual variation has been identified for the CYP2C9 activity and for the clinical response to the therapeutics metabolised by the enzyme. So far, at least 33 variants of CYP2C9 (*2 through to *34) have been identified. CYP2C9 is one of the clinically significant drug metabolising enzymes that demonstrates genetic variants with significant phenotype and clinical outcomes. This review updates our current knowledge on the polymorphic metabolism of drugs by CYP2C9 and discusses its implications in drug development. The authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Genetics Abstracts (CSA), SCOPUS, Chemical Abstracts, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to October 31 2010). A comprehensive literature search has identified 32 drugs that are subject to CYP2C9-mediated polymorphic metabolism. Drugs that are subject to polymorphic metabolism with clinical significance include nine nonsteroidal anti-inflammatory agents, six sulfonylurea antidiabetic drugs and, most critically, three oral coumarin anticoagulants. Polymorphisms in CYP2C9 have the potential to affect the clearance and clinical response of CYP2C9 substrate drugs with low therapeutic indices such as warfarin, phenytoin, and certain antidiabetic drugs. Warfarin has served as a model drug of how pharmacogenetics can be employed to achieve maximum efficacy and minimum toxicity. Minimizing interindividual variability in drug exposure due to CYP2C9 polymorphisms is an important goal in drug development and discovery.





Keywords: CYP2C9; clearance; drug development; polymorphism; toxicity

Document Type: Research Article

DOI: https://doi.org/10.2174/092986711794480131

Publication date: 2011-02-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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