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

作　　者：Si-hyung YANG Young-ah CHO Jun-shik CHOI 

机构地区：[1]College of Medicine, Dankook University, Cheonan 330-714, Korea [2]College of Medicine, Research Institute of Life Science, Gyeong-sang National University, Jinju 660-701, Korea [3]College of Pharmacy, Chosun University, Gwangju 501-759, Korea

出　　处：《Acta Pharmacologica Sinica》2011年第7期967-972,共6页中国药理学报（英文版）

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

关 键 词：PHARMACOKINETICS Iosartan EXP-3174 TICLOPIDINE CYP2C subfamily CYP3A P-GLYCOPROTEIN 

分 类 号：S858.23[农业科学—临床兽医学] S859.796[农业科学—兽医学]