Cimetidine-nicoumalone interaction in man: stereochemical considerations

Abstract

1. The cimetidine-nicoumalone interaction was studied in five subjects who received a single 10 mg oral dose of racemic nicoumalone alone and 3 days into an oral regimen of cimetidine of 200 mg three times daily and 400 mg at night. 2. The concentrations of R(+)- and S(-)-nicoumalone in plasma were measured using a stereospecific h.p.l.c assay; augmentation of prothrombin time was used as a measure of response. 3. Cimetidine increased the rate (but not extent) of absorption of both R(+)- and S(-)-nicoumalone, and reduced the clearance of R(+)-nicoumalone but not that of the S(-)-enantiomer. 4. Cimetidine increased the anticoagulant response produced by nicoumalone in some but not all subjects, despite a consistent effect on the pharmacokinetics of the oral anti-coagulant. 5. Cimetidine appears to produce its effect by stereoselectively inhibiting the elimination of R(+)-nicoumalone.