How is warfarin (Coumadin) metabolized?

Warfarin Metabolism

Warfarin is metabolized almost entirely by hepatic cytochrome P450 enzymes into inactive hydroxylated metabolites, with the more potent S-enantiomer primarily metabolized by CYP2C9 and the R-enantiomer metabolized by multiple CYP enzymes including CYP3A4, CYP1A2, and CYP1A1. 1

Enantiomer-Specific Metabolism

Warfarin exists as two optically active stereoisomers that are metabolized through distinct pathways:

S-Warfarin (More Potent Isomer)

• The S-enantiomer is 2-5 times more pharmacologically active than the R-enantiomer 2, 1
• Metabolized primarily by CYP2C9 in the liver cytochrome P450 complex 2
• Converted to 7-hydroxywarfarin as the predominant metabolite 2
• The metabolites are excreted in bile 2
• CYP2C9 is the principal hepatic P-450 enzyme modulating warfarin's in vivo anticoagulant activity 1

R-Warfarin (Less Potent Isomer)

• Metabolized by multiple CYP enzymes including CYP1A1, CYP1A2, CYP3A4, CYP2C8, CYP2C18, and CYP2C19 2, 1
• Converted primarily to 6-, 8-, and 10-hydroxywarfarin 3
• The metabolites are excreted in urine 2
• Has only 20-30% of the anticoagulant effect of S-warfarin 2

Pharmacokinetic Properties

Absorption and Distribution

• Warfarin is completely absorbed orally with essentially 100% bioavailability 2
• Peak blood concentrations occur within 90 minutes to 4 hours after oral administration 2, 1
• 98-99% is bound to plasma proteins, mainly albumin 2, 1
• Distributes into a small apparent volume of distribution of approximately 0.14 L/kg 1

Elimination

• Elimination half-life is 36-42 hours for racemic warfarin 2
• Elimination occurs almost entirely through hepatic metabolism to inactive metabolites 1
• Metabolites are principally excreted in urine and to a lesser extent in bile 1

Genetic Polymorphisms Affecting Metabolism

CYP2C9 Variants

Genetic polymorphisms in CYP2C9 significantly affect warfarin metabolism and dosing requirements:

• CYP2C92 and CYP2C93 are the major variant alleles with reduced enzymatic activity 2
• CYP2C9*2 occurs in approximately 11% of Caucasians 1
• CYP2C9*3 occurs in approximately 7% of Caucasians 1
• These variants occur at much lower frequencies in Asian populations (0% for *2 and 2-5% for *3) 4

Clinical impact of CYP2C9 variants:

• Patients with one variant allele (*1/*2 or *1/*3) have 37% reduced S-warfarin clearance compared to wild-type 1
• Patients with two variant alleles (*2/*2, *2/*3, or *3/*3) have 69% reduced S-warfarin clearance 1
• Patients with *1/*2 or *1/*3 genotype require 17% lower warfarin doses 2
• Patients with at least one *3 allele require 37% lower warfarin doses 2
• Variant alleles are associated with increased bleeding risk and prolonged hospitalization 5

VKORC1 Polymorphisms

• VKORC1 gene polymorphisms affect warfarin's pharmacodynamic target 2
• The -1639G>A promoter polymorphism and 1173C>T intron polymorphism affect warfarin dosing requirements 2
• These polymorphisms result in lower dose requirements for warfarin 1

Clinical Implications

Drug Interactions

Warfarin metabolism is susceptible to numerous drug interactions:

• Drugs inhibiting CYP2C9 (such as sulfamethoxazole and metronidazole) potentiate warfarin's effect 2
• CYP3A4 inhibitors affect R-warfarin metabolism 2
• Drugs that induce hepatic metabolism (barbiturates, rifampicin, carbamazepine) reduce warfarin's anticoagulant effect 6
• Over 500 distinct warfarin drug interactions have been reported 2

Monitoring Considerations

• The anticoagulant effect generally occurs within 24 hours but peak effect may be delayed 72-96 hours 1
• This delay reflects the time needed to deplete existing vitamin K-dependent clotting factors 1
• More frequent INR monitoring is needed when initiating or discontinuing interacting medications 2