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Interindividual variability in sensitivity to warfarin--Nature or nurture?
R Loebstein1, H Yonath, D Peleg
1Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Tel Hashomer, Israel.
Clinical Pharmacology and Therapeutics
|August 15, 2001
Summary
Warfarin sensitivity is influenced by cytochrome P4502C9 (CYP2C9) genotype and age, not vitamin K levels. Understanding these factors helps optimize warfarin dosing for patients.
Area of Science:
- Pharmacogenomics
- Clinical Pharmacology
- Drug Metabolism
Background:
- Interindividual variability in warfarin response is significant.
- Factors include diet, drug interactions, age, and CYP2C9 genetic polymorphisms (2C9*2, 2C9*3).
- These polymorphisms affect S-warfarin metabolism.
Purpose of the Study:
- To quantify the effects of age, CYP2C9 genotype, plasma warfarin and vitamin K levels, and medications on warfarin maintenance doses.
- To analyze these factors in 156 patients at stable anticoagulation.
Main Methods:
- Quantified relative effects of age and CYP2C9 genotype.
- Measured plasma warfarin and vitamin K concentrations.
- Assessed concurrent medications in 156 patients.
Main Results:
- CYP2C9 allele frequencies: CYP2C9*1 (0.84), CYP2C9*2 (0.10), CYP2C9*3 (0.06).
- Warfarin doses varied significantly by genotype (P < .0001) and age (P < .001), decreasing with age.
- Warfarin maintenance doses were independently associated with plasma warfarin levels, age, and CYP2C9 genotype, but not plasma vitamin K.
Conclusions:
- Individual warfarin sensitivity at steady state is determined by CYP2C9 genotype and age.
- Vitamin K levels do not significantly affect warfarin sensitivity in this context.
- Further prospective studies are needed to confirm clinical impact.
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