Altered pharmacokinetics of R ‐ and S ‐acenocoumarol in a subject heterozygous for CYP2C9*3

Objective Our objective was to study the pharmacokinetics of R ‐ and S ‐acenocoumarol in a subject who was highly sensitive to the anticoagulant effect of acenocoumarol. The subject was found to be heterozygous for CYP2C9*3 . Methods The plasma pharmacokinetics of the acenocoumarol enantiomers was established after an oral dose of 8 mg of racemic acenocoumarol. Urine was collected to establish the formation clearance of the 6‐ and 7‐hydroxy metabolites of R ‐ and S ‐acenocoumarol. Results The pharmacokinetics of S ‐acenocoumarol in this subject differed greatly (oral clearance, 6%‐10% half‐life of elimination, 400%‐500%) from the values of a [wt/wt] control and from population values. R ‐acenocoumarol clearance was at the lower level of population values. The apparent formation clearances of the metabolites were low‐approximately 10% of control activity for the hydroxylations (6‐ and 7‐) of S ‐acenocoumarol and for the 7‐hydroxylation of R ‐acenocoumarol. The rate of the 6‐hydroxylation of R ‐acenocoumarol was about 50% of control values. Conclusion The presence of even one copy of CYP2C9*3 reduces profoundly the metabolic clearance of S ‐acenocoumarol. As a result the first‐pass effect of elimination is abolished and the maintenance time is increased. S ‐Acenocoumarol, which is normally clinically inactive, will now exert main anticoagulant activity. Clinical Pharmacology & Therapeutics (2001) 70 , 292–298; doi: 10.1067/mcp.2001.117936