CYP2C9 is a phase I drug-metabolizing cytochrome P450 (CYP450) enzyme isoform that plays a major role in the oxidation of both xenobiotic and endogenous compounds. Gray et al. identified CYP2C9 as one of several CYP2C genes clustered in a 500 kb region on chromosome 10q24.

The cluster comprises four genes arranged in the order CYP2C8-CYP2C9-CYP2C19-CYP2C18. Several studies identified a single nucleotide polymorphism (SNP) linkage between the CYP2C8 and CYP2C9 genes. CYP2C9 is primarily expressed in the liver, and the expression level is reported to be the second-highest among CYP isoforms. Only the CYP enzyme CYP3A4 is quantitatively more highly expressed in the human liver.


It has been estimated that CYP2C9 is responsible for the metabolic clearance of up to 15-20% of all drugs undergoing phase I metabolism. Table 1 is a partial list showing examples of the broad substrate spectrum of drugs that are metabolized by CYP2C9, including relevant references. Further information is also available at and in the following reviews.

Inducer and inhibitors

CYP2C9 is induced by rifampicin. Treatment with rifampicin has been shown consistently to increase the clearance of drugs eliminated by CYP2C9. The clearance of losartan, phenytoin, tolbutamide, and S-warfarin is approximately doubled in healthy volunteers or patients treated with rifampicin.

CYP2C9 is inhibited by amiodarone, fluconazole, and sulfate azole among other drugs. Dangerous drug-drug interaction can arise when an inhibitor such as one of these is added to a therapeutic regime that includes drugs with a low therapeutic index, such as S-warfarin, tolbutamide, and phenytoin [40-42]. For example, there are numerous studies documenting the potentiation of the anticoagulant effect of warfarin in patients coadministered with amiodarone.


CYP2C9 is the enzyme responsible for the metabolism of the S-isomer of warfarin that is principally responsible for the anticoagulant effect of the drug. The crystal structure of human CYP2C9 was described by Williams et al. for both CYP2C9 in complex with warfarin and unliganded CYP2C9 (Protein Data Bank ID: 1OG2 and 1OG5, respectively).

The structure showed unanticipated interactions between CYP2C9 and warfarin, revealing a new binding pocket, suggesting that CYP2C9 may simultaneously accommodate multiple ligands during its biological function. Structural analysis suggested that CYP2C9 may undergo an allosteric change when binding warfarin. An X-ray crystal structure of CYP2C9, in complex with the NSAID flurbiprofen, has also been described (Protein Data Bank ID: 1R9O).

Genetic phenotypes and adverse drug reactions

The gene coding for the CYP2C9 enzyme is highly poly- morphic, including functional variants of major pharmacogenetic importance. Changes in metabolic activity caused by genetic variants in CYP2C9 play a major role in pathogenesis caused by adverse drug reactions. Patients with low enzyme activity are at risk of adverse drug reaction, especially for CYP2C9 substrates with a narrow therapeutic window, such as S-warfarin, phenytoin, glipizide, and tolbutamide.

A large body of literature investigates two common non-synonymous variants within CYP2C9 (R144C, rs1799853, and I359L, rs1057910), leading to poor metabolism phenotypes. Both variants have significantly lower frequencies in African and Asian populations compared with Caucasian populations, see frequency tables (Tables ​(Tables22 and ​and3)3) below.

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