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

Abstract

npg IntroductionLosartan (DuP 753,, an angiotensin II receptor antagonist, has a low side-effect profile and is approved for the treatment of hypertension, alone or in combination with other agents [1] . After oral administration, losartan is almost completely absorbed and extensively metabolized to a carboxylic acid derivative, EXP-3174, mainly by cytochrome P450 (CYP) 2C9 and 3A4 [2] . EXP-3174 is a major active metabolite in both rats and humans and is a more potent inhibitor of angiotensin II receptor than losartan, with high-affinity receptor specificity [3] . Losartan has also been reported to be a substrate of P-glycoprotein (P-gp) [4] . Considering that losartan is a substrate of both CYP enzymes and P-gp, the modulation of CYP and P-gp activities may cause significant changes in the pharmacokinetic profiles of losartan and its active metabolite, EXP-3174.Ticlopidine, a potent antiplatelet agent induced by adenosine diphosphate, is used for the treatment of a variety of platelet-dependent disease states [5] . Several papers recommend ticlopidine as a valuable alternative when patients cannot tolerate aspirin [6,7] . It has been reported that ticlopidine causes significant inhibition of several drugs metabolized by the hepatic CYP enzyme system [8,9] .Clinically, losartan and ticlopidine can be prescribed concomitantly for the prevention or therapy of cardiovascular diseases. However, the pharmacokinetic interaction between ticlopidine and losartan in vivo has not yet been reported. Therefore, the present study aimed to evaluate the effect of ticlopidine on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats. The effects of ticlopidine on P-gp, CYP2C9, and 3A4 activities were also evaluated. Materials and methods ChemicalsLosartan, EXP-3174, L-158.809 (internal standard), acetonitrile, methanol, and tert-butylmethylether were purchased from Merck Corporation (Darmstadt, Germany). Ticlopidine was purchased from Sigma-Aldrich Corporation (St Louis, MO, USA). All other chemicals were of reagent grade, and all solvents were of HPLC grade. Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in ratsSi-hyung YANG 1 , Young-ah CHO 2 , Jun-shik CHOI 3, * 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. Ticlopid...

The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo

“… 78 According to in vitro studies, E-3174 is also formed by the action of CYP3A4, 79 , 80 but in vivo studies with therapeutic doses of losartan showed no significant contribution to losartan CYP3A4 metabolism. 81 The predominant contribution of CYP2C9 to losartan metabolism was confirmed indirectly by a decrease in the AUC of E-3174 when it was used in combination with moderate inhibitor CYP2C9 (fluconazole), while no change in AUC of E-3174 was observed when losartan was used in combination with a strong CYP3A4 inhibitor (itraconazole). 47 In many studies, losartan has been safely used as a marker substrate for phenotyping CYP2C9 activity.…”

Effects of licochalcone A on the bioavailability and pharmacokinetics of nifedipine in rats: possible role of intestinal CYP3A4 and P‐gp inhibition by licochalcone A

“…The inhibitory effect of licochalcone A (IC 50 = 5.9 μM) on CYP3A4 was weaker than that of ketoconazole (IC 50 = 0.1 μM) externally. In general, when the inhibitory effect (IC 50 ) of CYP3A4 was below 20 μM, the bioavailability (AUC) of CYP3A4 substrates were increased by only CYP3A4 inhibitors [43][44][45].…”

Effects of Ginkgo leaf tablets on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its mechanism

“… 2008 ; Yang et al. 2011 ). Losartan is mainly metabolized by cytochrome P450 enzymes CYP3A4 and CYP2C9, and therefore, modulation of CYP3A4 or CYP2C9 activities may cause significant changes in the pharmacokinetic profiles of losartan and its active metabolite EXP3174 (Li et al.…”