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J. Pers. Med. 2018, 8(1), 1; https://doi.org/10.3390/jpm8010001

Pharmacogenomics of CYP2C9: Functional and Clinical Considerations

1
Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
2
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA
3
Department of Genome Sciences and Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
4
Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide 5042, Australia
*
Author to whom correspondence should be addressed.
This article is contributed by members of the IUPHAR (International Union of Basic and Clinical Pharmacology) Drug Metabolism and Drug Transporter Section Executive Committee.
Received: 31 October 2017 / Revised: 18 December 2017 / Accepted: 20 December 2017 / Published: 28 December 2017
(This article belongs to the Special Issue Cytochrome P450 Variation in Pharmacogenomics)
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Abstract

CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare ‘variants of uncertain significance’, which are increasingly detected as more exome and genome sequencing of diverse populations is conducted. View Full-Text
Keywords: CYP2C9; cytochrome P450; polymorphism; pharmacogenomics; warfarin CYP2C9; cytochrome P450; polymorphism; pharmacogenomics; warfarin
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Daly, A.K.; Rettie, A.E.; Fowler, D.M.; Miners, J.O. Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. J. Pers. Med. 2018, 8, 1.

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