Implications of cytochrome P450 2C9 polymorphism on warfarin metabolism and dosing.
Warfarin is an anticoagulant available as a racemic mixture. The R- and S-isomers differ with respect to relative plasma concentrations, clearance, potency, sites of metabolism, and cytochrome P450 (CYP) isoenzymes responsible for metabolism. S-Warfarin, the more potent isomer, is metabolized primarily by CYP2C9. Genetic polymorphisms resulting from single amino acid substitutions reduce the metabolic capability of 2C9. A reduction in warfarin metabolism due to genetic polymorphism may explain the increased warfarin response and bleeding episodes in some patients. Clinical studies showed an increased plasma level of S-warfarin, decreased clearance of S-warfarin, increased frequency of bleeding, and prolongation of hospitalization in patients with variant CYP2C9 alleles. Adverse outcomes associated with warfarin possibly could be avoided by identifying patients with variant alleles before therapy and starting therapy at low dosages.
Redman
A R
AR
Department of Pharmacy Practice, Mercer University Southern School of Pharmacy, Atlanta, Georgia 30341, USA.
D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry; D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D011110:Polymorphism, Genetic / Q000235:genetics*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D014859:Warfarin / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry
D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase