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Pharmacoepidemiology and drug utilization: Interindividual variability in sensitivity to warfarin - Nature or nurture?
Year:
2001
Authors :
Ezra, David
;
.
Volume :
70
Co-Authors:
Loebstein, R., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Yonath, H., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Peleg, D., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Almog, S., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Rotenberg, M., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Lubetsky, A., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Roitelman, J., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Harats, D., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Halkin, H., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Ezra, D., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel, Division of Clinical Pharmacology and Toxicology, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Facilitators :
From page:
159
To page:
164
(
Total pages:
6
)
Abstract:
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) (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.
Note:
Related Files :
adult
aging
Blood
cytochrome P450
Female
Genetics
Male
quantitative assay
Variation (Genetics)
vitamin K group
Show More
Related Content
More details
DOI :
10.1067/mcp.2001.117444
Article number:
Affiliations:
Database:
Scopus
Publication Type:
article
;
.
Language:
English
Editors' remarks:
ID:
22088
Last updated date:
02/03/2022 17:27
Creation date:
16/04/2018 23:49
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Scientific Publication
Pharmacoepidemiology and drug utilization: Interindividual variability in sensitivity to warfarin - Nature or nurture?
70
Loebstein, R., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Yonath, H., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Peleg, D., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Almog, S., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Rotenberg, M., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Lubetsky, A., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Roitelman, J., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Harats, D., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Halkin, H., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel
Ezra, D., Division of Clinical Pharmacology and Toxicology and the Anticoagulation Clinic, Department of Medicine, The Chaim Sheba Medical Center, Israel, Division of Clinical Pharmacology and Toxicology, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Pharmacoepidemiology and drug utilization: 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. 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) (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.
Scientific Publication
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