Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

Aim: Losartan and antiplatelet agent ticlopidine can be prescribed concomitantly for prevention or therapy of cardiovascular diseases. Hence, the effects of ticlopidine on the pharmacokinetics of losartan and its active metabolite EXP-3174 were evaluated in rats.

Methods: Ticlopidine (4 or 10 mg/kg po) was administered 30 min before administration of losartan (9 mg/kg po or 3 mg/kg iv). The activity of human CYP2C9 and 3A4 were measured using the CYP inhibition assay kit. The activity of P-gp was evaluated using rhodamine-123 retention assay in MCF-7/ADR cells.

Results: Ticlopidine (10 mg/kg) significantly increased the areas under the plasma concentration-time curves (AUCs) and peak plasma concentration (C(max)) of oral losartan (9 mg/kg), as well as the AUCs of the active metabolite EXP-3174. Ticlopidine (10 mg/kg) did not significantly change the pharmacokinetics of intravenous losartan (3 mg/kg). Ticlopidine inhibited CYP2C9 and 3A4 with IC₅₀ values of 26.0 and 32.3 μmol/L, respectively. The relative cellular uptake of rhodamine-123 was unchanged.

Conclusion: The significant increase in the AUC of losartan (9 mg/kg) by ticlopidine (10 mg/kg) could be attributed to the inhibition of CYP2C9- and 3A4-mediated losartan metabolism in small intestine and/or in liver. The inhibition of P-gp in small intestine and reduction of renal elimination of losartan by ticlopidine are unlikely to be causal factors.