Pharmacogenetics of warfarin: current status and future challenges

Area of Science:

• Pharmacogenomics
• Drug Metabolism
• Clinical Pharmacology

Background:

• Warfarin, an anticoagulant, presents challenges in dosing due to significant interindividual variability and bleeding risks.
• Its mechanism involves inhibiting vitamin K recycling, impacting clotting factor activation.
• Genetic and environmental factors contribute to the wide range of required warfarin doses.

Purpose of the Study:

• To review genes influencing warfarin's pharmacokinetics and pharmacodynamics.
• To highlight the roles of CYP2C9 and VKORC1 in warfarin response.
• To discuss the potential for genotype-guided warfarin therapy.

Main Methods:

• Review of literature on genes affecting warfarin biotransformation and action.
• Identification of key genes, including CYP2C9 and VKORC1.
• Discussion of environmental factors influencing warfarin dose.

Main Results:

• Thirty genes potentially involved in warfarin's action and metabolism were identified.
• CYP2C9 and VKORC1 are the most significant genes affecting warfarin's pharmacokinetic and pharmacodynamic parameters.
• Interindividual variations in warfarin dose are partly explained by these genes and environmental factors.

Conclusions:

• CYP2C9 and VKORC1, along with environmental influences, are crucial for understanding warfarin dose variability.
• Ongoing research into genetic and environmental factors will improve warfarin dose prediction.
• Pre-prescription genotyping for individualized warfarin therapy offers a promising approach to minimize bleeding risks while maintaining efficacy.