Evaluation of a potential enantioselective interaction between ticlopidine and warfarin in chronically anticoagulated patients

Ticlopidine is a novel antiplatelet drug reported to cause significant inhibition of several drugs metabolized by the hepatic cytochrome P-450 enzyme system, including antipyrine and theophylline. Warfarin, a racemic mixture of two enantiomers (R and S), is extensively metabolized by the CYP-450 system. S-Warfarin is five to eight times as active as R-warfarin. The effects of ticlopidine on the pharmacokinetics and pharmacodynamics of warfarin were examined in nine elderly men (69±4 years) receiving long-term warfarin therapy. Steady-state warfarin enantiomer concentrations and International Normalized Ratios (INRs) were determined at baseline and after 14 days of treatment with oral ticlopidine, 250 mg twice daily. Warfarin enantiomer serum concentrations were determined by high-performance liquid chromatography after chiral derivitization. Ticlopidine co-medication resulted in a significant increase in mean R-warfarin concentrations (+25.7%, p<0.05), while no significant difference in S-warfarin concentrations was noted (+0.8%). Mean INR values were not significantly different from the baseline (+8.3%), although substantial interindividual variability was noted. We conclude that ticlopidine co-medication does result in an enantioselective kinetic interaction with warfarin; however, this interaction is likely to be of minimal clinical significance in most patients