Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance

Clin Pharmacol Ther. 2002 Dec;72(6):702-10. doi: 10.1067/mcp.2002.129321.

Abstract

Objective: Our objective was to determine the influence of cytochrome P450 (CYP) 2C9 and CYP2C19 genetic polymorphisms on warfarin dose requirement and metabolic clearance.

Methods: The study population consisted of 93 Italian outpatients receiving long-term warfarin anticoagulant therapy (international normalized ratio values, 2-3), divided into 3 dose groups: low (<26.25 mg/wk; n = 37), medium (26.25-43.75 mg/wk; n = 32), and high (>43.75 mg/wk; n = 24). Steady-state unbound plasma concentrations of S- and R-warfarin were measured by HPLC and equilibrium dialysis, and corresponding unbound oral clearance (CL(free)) values were calculated. Allelic variants of CYP2C9 (CYP2C9(*)2 and CYP2C9(*)3) and CYP2C19 (CYP2C19(*)2) were identified by polymerase chain reaction, followed by restriction enzyme analysis.

Results: Fifty-four patients carried no CYP2C9 mutated alleles ((*)1/(*)1), 31 carried one ((*)1/(*)2, n = 15; and (*)1/(*)3, n = 16), and 8 carried two ((*)2/(*)2, n = 2; (*)3/(*)3, n = 2; and (*)2/(*)3, n = 4). Two subjects were homozygous and 19 were heterozygous for the CYP2C19(*)2 allele variant. The frequencies of CYP2C9 mutated alleles were 72% in the low-dose group, 36% in the medium-dose group, and 4% in the high-dose group; the corresponding mean S-warfarin CL(free) values were 307.5 mL/min, 480.3 mL/min, and 881.3 mL/min. The mean S-warfarin CL(free) values varied significantly among the CYP2C9 genotype groups (P <.0001), although most patients (72%) with no mutated alleles showed S-warfarin CL(free) values in the same range as those carrying mutated alleles (58-777 mL/min). No relationship was found between S-warfarin CL(free) and CYP2C19 genotype or between R-warfarin CL(free) and either CYP2C9 or CYP2C19 genotype.

Conclusion: CYP2C9 genetic polymorphisms markedly influence warfarin dose requirements and metabolic clearance of the S-warfarin enantiomer, although nongenetic factors may also contribute to their large interindividual variability.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Anticoagulants / administration & dosage
  • Anticoagulants / pharmacokinetics*
  • Anticoagulants / pharmacology*
  • Aryl Hydrocarbon Hydroxylases / drug effects*
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2C9
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Genotype
  • Humans
  • Isomerism
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Mixed Function Oxygenases / drug effects*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Restriction Mapping
  • Warfarin / administration & dosage
  • Warfarin / pharmacokinetics*
  • Warfarin / pharmacology*
  • Whites / genetics*

Substances

  • Anticoagulants
  • Warfarin
  • Mixed Function Oxygenases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19