Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose.
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)=0.37). The same factors, except for age, significantly influenced S-warfarin clearance (adjusted R(2)=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.
Herman
D
D
Institute of Biochemistry, Faculty of Medicine, Ljubljana, Slovenia.
Locatelli
I
I
Grabnar
I
I
Peternel
P
P
Stegnar
M
M
Mrhar
A
A
Breskvar
K
K
Dolzan
V
V
D000368:Aged; D000375:Aging / Q000502:physiology; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001798:Blood Proteins / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D065729:Cytochrome P-450 CYP2C9; D003710:Demography; D004347:Drug Interactions; D005260:Female; D018565:Food-Drug Interactions; D005838:Genotype; D006350:Heart Valve Prosthesis; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D012044:Regression Analysis; D012709:Serum Albumin / Q000378:metabolism; D013237:Stereoisomerism; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D000925:Anticoagulants; D001798:Blood Proteins; D012709:Serum Albumin; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases