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-4 50 enzyme system, including antipyrine and theophylline. Warfarin, a r acemic mixture of two enantiomers (R and S), is extensively metabolize d by the CYP-450 system. S-Warfarin is five to eight times as active a s R-warfarin. The effects of ticlopidine on the pharmacokinetics and p harmacodynamics of warfarin were examined in nine elderly men (69 +/- 4 years) receiving long-term warfarin therapy. Steady-state warfarin e nantiomer concentrations and International Normalized Ratios (INRs) we re determined at baseline and after 14 days of treatment with oral tic lopidine, 250 mg twice daily. Warfarin enantiomer serum concentrations were determined by high-performance liquid chromatography after chira l derivitization. Ticlopidine co-medication resulted in a significant increase in mean R-warfarin concentrations (+25.7%, p < 0.05), while n o 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. W e conclude that ticlopidine co-medication does result in an enantiosel ective kinetic interaction with warfarin; however, this interaction is likely to be of minimal clinical significance in most patients.