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
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs are among the most commonly used analgesics. There are over 40 NSAID drugs marketed worldwide. Although some NSAIDs are considered safe for over-the-counter use, they have the potential to cause severe gastrointestinal, renal and cardiovascular adverse reactions (ADRs)6. Substantial evidence links CYP2C9 polymorphisms to metabolism and clearance of several drugs in the class, such as celecoxib, flurbiprofen, ibuprofen, and meloxicam. Several studies have established an association of CYP2C9 reduced or no function alleles and elevated NSAID exposure, which potentially increases the risk of adverse events7,8. CPIC provides therapeutic recommendations for NSAIDs based on CYP2C9 genotypes. The population exposed to NSAIDs worldwide is large, and thus using pharmacogenomics information of CYP2C9 to guide dosing and selection can potentially reduce adverse events and improve public health.
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References
- Van, BD., et al., Cytochrome P450 2C9-CYP2C9. Pharmacogenetics and genomics. 2010.
- Whirl-Carrillo M., et al., Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 92 (4): 414-417
- 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.
- Thorn CF., et al., PharmGKB summary: phenytoin pathway. Pharmacogenetics and genomics. 2012
- 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.
- Harirforoosh, S., et al., Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J of Pharm and Pharm Sci. 2013; 16 (5): 821-847.
- Lee CR., et al., Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. Euro J of clin pharmacol. 2003 (12): 791-4.
- Perini JA. et al. Influence of CYP2C9 genotypes on the pharmacokinetics and pharmacodynamics of piroxicam. Clin Pharmacol Ther. 2005; 78 (4): 362-9.