Metabolism of ticlopidine in rats: identification and quantitative determination of some its metabolites in plasma, urine and bile.

The fate of Ticlopidine, a new inhibitor of platelet aggregation, has been studied in rats following single oral doses. The compound was quickly absorbed as evaluated by the time of the peak plasma concentration. The metabolism of Ticlopidine involved N-oxidation, cleavage of the N-C bond, oxidation of aliphatic carbon followed by glycine conjugation. Methods for quantitation of Ticlopidine and of its metabolites, Ticlopidine-N-oxide, Tetrahydrothienopyridine, 2-cloro-hippuric acid, and the metabolite named Ticlopidine-M, are reported. Urinary excretion took place essentially in the first 24 hours and biliary excretion was most pronounced in the hour following dosing. Small amounts of Ticlopidine were excreted unchanged. The major urinary metabolites were 2-chlorohippuric acid (16% of the dose) and tetrahydrothienopyridine (8%), while Ticlopidine-M predominated in the bile (2% in 0.5h). The peak plasma concentration of Ticlopidine occurred at 0.5 hour. The plasma concentration/time curve displayed a biphasic profile and the terminal half-life of Ticlopidine was tentatively estimated to be 6-10 h in the rat. Ticlopidine-N-oxide was also quantified in plasma: the levels were inferior to those of Ticlopidine throughout the experimental period.