Gene Description

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Gene Description

CYP2C9

CYP2C9 is a hepatic cytochrome P450 (CYP450) enzyme playing major roles in the metabolism of many clinically relevant drugs, such as warfarin, phenytoin, and acenocoumarol.1 Clinical Pharmacogenetic Implementation Consortium (CPIC) has issued guidelines for warfarin and phenytoin dosing based on CYP2C9 genotypes.

Warfarin

Warfarin is the most commonly used oral anticoagulant worldwide. Warfarin dosing is especially challenging mainly due to its narrow therapeutic index and wide interpatient variability in pharmacokinetics. Several genes have been associated with the observed interpatient variability.2 Among all, CYP2C9, VKORC1, and CYP4F2 show the strongest evidence and are used by CPIC to provide recommendations for warfarin dosing.3

Phenytoin

Phenytoin is a widely used antiepileptic drug. Phenytoin dosing is challenging mainly due to its narrow therapeutic index and wide interpatient variability in pharmacokinetics. The interpatient variability is partly attributed to the genetic variants in CYP2C9.2,4 Some CYP2C9 alleles are associated with lower intrinsic clearance, classified as intermediate metabolizer (IM) or poor metabolizer (PM). The IM and PM patients are thought to have higher risk for exposure-related toxicities than the normal metabolizers. The CPIC guideline recommends treatment and dosing adjustment for phenytoin based on the genotypes of CYP2C9 and HLA-B.5

 

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References
  1. Van BD, et al. Cytochrome P450 2C9-CYP2C9. Pharmacogenet Genom. 2010.
  2. Whirl-Carrillo M, et al. Pharmacogenomics Knowledge for Personalized Medicine. Clin Pharmacol Ther. 2012;92(4):414-17.
  3. Johnson JA, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-guided Warfarin Dosing: 2017 Update Clin Pharmacol Ther. 2017;102(3):397-404.
  4. Thorn CF, et al. PharmGKB Summary: Phenytoin Pathway. Pharmacogenet Genom. 2012
  5. Caudle KE, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing. Clin Pharmacol Ther. 2014;96(5):542-8.