Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose

Abstract

Warfarin is an anticoagulant drug with narrow therapeutic index and high interindividual variability in dose requirement. S-warfarin is metabolized mainly by polymorphic cytochrome P450 (CYP) 2C9. We systematically quantified the influence of CYP2C9 genotype, demographic factors and concomitant drug treatment on warfarin metabolism and maintenance dose. The mean warfarin doses were lower in carriers of one (2.71 mg/day, 59 patients) and two polymorphic alleles (1.64 mg/day, 11 patients) than in carriers of two wild-type alleles (4.88 mg/day, 118 patients). Multiple regression analysis demonstrated that CYP2C9 genotype, age, concomitant treatment with warfarin metabolism inducers and lean body weight contributed significantly to interindividual variability in warfarin dose requirement (adjusted R 2 ¼ 0.37). The same factors, except for age, significantly influenced S-warfarin clearance (adjusted R 2 ¼ 0.42). These results can serve as a starting point for designing prospective studies in patients in the initiation phase of genotype-based warfarin therapy.

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

“…However, most of these efforts have focused on populations of European descent. [11][12][13][14][15][16][17][18]Herein we report CYP2C9 allele frequencies among European American and African American patients and evaluate the influence of CYP2C9 on warfarin dose stratified by race. We detail genotyping methodology and describe study design and cohort characteristics at enrollment.…”

Building Individualized Medicine: Prevention of Adverse Reactions to Warfarin Therapy

“…This finding was confirmed multiple times in different populations (for recent works, see Herman et al, 2005;Voora et al, 2005;Loebstein et al, 2006;Obayashi et al, 2006;Tham et al, 2006); several review articles summarized these observations (Daly and King, 2003;Palkimas et al, 2003;Wadelius and Pirmohamed, 2006). Although CYP2C9 is the major catalyst responsible for biotransformation of warfarin and a closely related acenocoumarol, CYP2C9-catalyzed metabolism of another warfarin analog, phenprocoumon, is less important.…”

Pharmacogenetics and pharmacogenomics: origin, status, and the hope for personalized medicine

“…Various other tests are potentially useful and are occasionally but not regularly used. For instance, metropolol tends to cause bradycardia when the cytochrome CYP2D6 is missing, 49 or there is a relationship between warfarin-induced bleeding events and CYP2C9 activity, 50 or isoniacid causes unpleasant effects when Nacetyltransferase activity is lacking. 51 Thus, some cases of clinical usefulness of pharmaco-genetics and -genomics are well established.…”