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

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Yang SH, Cho YA, Choi JS

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

Acta Pharmacol Sin. 2011 Jul;32(7):967-72. doi: 10.1038/aps.2011.32. Epub 2011 Jun 13.

PubMed ID

21666702 [ View in PubMed

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Abstract

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 IC(5)(0) values of 26.0 and 32.3 mumol/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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Ticlopidine	Cytochrome P450 2C9	Protein	Humans	Unknown	Inhibitor	Details