Pharmacoepidemiology and drug utilization: Interindividual variability in sensitivity to warfarin - Nature or nurture?

Ronen Loebstein, Hagith Yonath, Daria Peleg, Shlomo Almog, Michal Rotenberg, Aharon Lubetsky, Joseph Roitelman, Dror Harats, Hillel Halkin*, David Ezra

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

245 Scopus citations


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. Patients and 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 ≥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 ≤65 years old bearing the CYP2Cg*1 allele (P < .001). On multiple regression, warfarin maintenance doses were independently associated with plasma warfarin (reflecting its metabolic clearance) (r2 = 0.26), age (possibly reflecting increased intrinsic sensitivity) (r2 = 0.12), and genotype (reflecting S-warfarin levels) (r2 = 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.

Original languageEnglish
Pages (from-to)159-164
Number of pages6
JournalClinical Pharmacology and Therapeutics
Issue number2
StatePublished - 2001
Externally publishedYes


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