CYP2C9

CYP2C9 is a member of the cytochrome P450 superfamily of heme-containing monooxygenases. It is primarily expressed in the liver, with some expression in the intestine, and contributes to the oxidative metabolism of a wide range of endogenous compounds and xenobiotics. As part of Phase I metabolism, CYP2C9 catalyzes reactions that often modify drugs to more water-soluble forms for further processing and elimination.

CYP2C9 metabolizes many clinically important drugs. Notable substrates include the S-enantiomer of warfarin, various nonsteroidal anti-inflammatory drugs such as diclofenac, ibuprofen, and naproxen, sulfonylurea antidiabetics like tolbutamide and glipizide, anticonvulsants such as phenytoin, and other medications such as losartan and meloxicam. Variation in CYP2C9 activity can significantly affect drug exposure and response, sometimes necessitating dose adjustments.

Genetic polymorphisms in CYP2C9 influence enzymatic activity. The most common reduced-activity alleles are CYP2C9*2 (430C>T, resulting in Arg144Cys) and CYP2C9*3 (1075A>C, resulting in Ile359Leu). These variants slow clearance of many substrates, increasing drug exposure and risk of adverse effects. Other population-specific alleles exist and contribute to variability in activity.

Clinical relevance and pharmacogenetics. Genetic testing for CYP2C9 can inform dosing strategies for warfarin and other substrates, helping to reduce bleeding risk or toxicity. Guidelines from pharmacogenetics consortia provide genotype-informed dosing recommendations for select drugs, reflecting the impact of CYP2C9 variability on therapeutic outcomes.

Drug interactions and regulation. CYP2C9 activity can be inhibited by agents such as amiodarone, fluconazole, metronidazole, and sulfamethoxazole-trimethoprim, which may raise substrate levels, or induced by compounds like rifampin, which can enhance metabolism. Such interactions further influence drug safety and efficacy.