Interindividual variability in sensitivity to warfarin--Nature or nurture?
BACKGROUND
Interindividual variability in responses to warfarin is attributed to dietary vitamin K, drug interactions, age, or genetic polymorphism in the cytochrome P4502C9 enzyme (CYP2C9) (allelic variants 2C9*2 and 2C9*3 ) linked with impaired metabolism of the potent enantiomere S-warfarin.


METHODS
We quantified the relative effects of age and of simultaneously determined CYP2C9 genotype, plasma warfarin and vitamin K concentrations, and concurrent medications on warfarin maintenance doses in 156 patients at optimized stable anticoagulation.


RESULTS
Allele frequencies for CYP2C9*1, CYP2C9*2, and CYP2C9*3 were 0.84, 0.10, and 0.06. Warfarin doses were 6.5 +/- 3.2, 5.2 +/- 2.4, and 3.3 +/- 2.0 mg/d in the 3 genotype groups (P < .0001). Warfarin doses decreased with age as follows: 7.7 +/- 3.7 versus 4.9 +/- 2.9 mg/d at < 50 years and >66 years (P < .001), mainly as a result of decreased plasma warfarin clearance (2.8 +/- 1.4 mL/min versus 1.9 +/- 0.8 mL/min; P < .001). Vitamin K (1.6 +/- 1.1 ng/mL) did not differ among the age or genotype groups. Patients >or=66 years old with the CYP2C9*3 allele required only 2.2 +/- 1.2 mg/d compared with 7.9 +/- 3.7 mg/d in those <or=65 years old bearing the CYP2C9*1 allele (P < .001). On multiple regression, warfarin maintenance doses were independently associated with plasma warfarin (reflecting its metabolic clearance) (r (2) = 0.26), age (possibly reflecting increased intrinsic sensitivity) (r (2) = 0.12), and genotype (reflecting S-warfarin levels) (r (2) = 0.10) but not with plasma vitamin K.


CONCLUSIONS
At optimized steady state, individual sensitivity to warfarin is determined by CYP2C9 genotype and age with no effect of vitamin K. Prospective studies will determine the impact of these findings in clinical practice.
Loebstein
R
R
Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Tel Hashomer, Israel.
Yonath
H
H
Peleg
D
D
Almog
S
S
Rotenberg
M
M
Lubetsky
A
A
Roitelman
J
J
Harats
D
D
Halkin
H
H
Ezra
D
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood / Q000235:genetics*; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D013237:Stereoisomerism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics*; D014812:Vitamin K / Q000097:blood; D014859:Warfarin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000925:Anticoagulants; D014812:Vitamin K; 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