Pharmacogenomics of CYP2C9: Functional and Clinical Considerations.

Article Details

Citation

Daly AK, Rettie AE, Fowler DM, Miners JO

Pharmacogenomics of CYP2C9: Functional and Clinical Considerations.

J Pers Med. 2017 Dec 28;8(1). pii: jpm8010001. doi: 10.3390/jpm8010001.

PubMed ID
29283396 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
CoumarinCytochrome P450 2C9ProteinHumans
No
Substrate
Details
Estrone sulfateCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Inhibitor
Details
EtodolacCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Details
WarfarinCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Inducer
Details
Drug Interactions
DrugsInteraction
Acenocoumarol
Hydroxyprogesterone caproate
The metabolism of Acenocoumarol can be increased when combined with Hydroxyprogesterone caproate.
Axitinib
Acetylsalicylic acid
The metabolism of Axitinib can be increased when combined with Acetylsalicylic acid.
Clomipramine
Norethisterone
The metabolism of Clomipramine can be increased when combined with Norethisterone.
Clomipramine
Hydroxyprogesterone caproate
The metabolism of Clomipramine can be increased when combined with Hydroxyprogesterone caproate.
Imipramine
Secobarbital
The metabolism of Imipramine can be increased when combined with Secobarbital.
Imipramine
Hydrocortisone
The metabolism of Imipramine can be increased when combined with Hydrocortisone.
Imipramine
Norethisterone
The metabolism of Imipramine can be increased when combined with Norethisterone.
Imipramine
Betamethasone
The metabolism of Imipramine can be increased when combined with Betamethasone.
Imipramine
Aminoglutethimide
The metabolism of Imipramine can be increased when combined with Aminoglutethimide.
Imipramine
Hydroxyprogesterone caproate
The metabolism of Imipramine can be increased when combined with Hydroxyprogesterone caproate.
Interactions
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