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.