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Interaction of angiotensin II type 1 receptor blockers with P-gp substrates in Caco-2 cells and hMDR1-expressing membranes.

机译:血管紧张素II 1型受体阻滞剂与Caco-2细胞和hMDR1表达膜中P-gp底物的相互作用。

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AIMS: The inhibitory effect of angiotensin II type 1 receptor blockers (ARBs) on P-glycoprotein (P-gp) was examined to evaluate their clinical drug-drug interaction (DDI) potential. MAIN METHODS: We performed an inhibition study on the vectorial transport of digoxin, a typical substrate for P-gp, using a human colonic adenocarcinoma cell line, Caco-2 cells, and verapamil-stimulated ATPase activity using human multidrug resistance 1 (hMDR1)-expressing membrane. KEY FINDINGS: The vectorial transport of digoxin was inhibited by candesartan cilexetil, irbesartan and telmisartan with the IC(50) values of 14.7, 34.0 and 2.19microM, respectively. Those values were 7.4-426-fold higher than their theoretical clinical gastrointestinal concentration [I] at doses in clinical DDI studies. Other ARBs failed to show interaction with P-gp. SIGNIFICANCE: It was demonstrated that candesartan cilexetil, irbesartan and telmisartan had the potential to inhibit the transport of various drugs via P-gp. Telmisartan, which caused an increase in the serum digoxin concentration in humans, had a sufficiently high [I]/IC(50) value, suggesting that DDI between digoxin and telmisartan was caused by the inhibition of digoxin efflux via intestinal P-gp.
机译:目的:研究血管紧张素II 1型受体阻滞剂(ARBs)对P-糖蛋白(P-gp)的抑制作用,以评估其临床药物相互作用(DDI)的潜力。主要方法:我们使用人结肠腺癌细胞系,Caco-2细胞和维拉帕米刺激的ATPase活性(使用人多药耐药性1(hMDR1))对地高辛(P-gp的典型底物)的载体运输进行了抑制研究。 -表达膜。主要发现:地高辛的向量运输受到坎地沙坦西拉克司,厄贝沙坦和替米沙坦的抑制,IC(50)值分别为14.7、34.0和2.19microM。在临床DDI研究中,这些值比其理论临床胃肠道浓度[I]高7.4-426倍。其他ARB无法显示与P-gp的相互作用。意义:证实坎地沙坦西酯,厄贝沙坦和替米沙坦具有抑制多种药物通过P-gp转运的潜力。替米沙坦引起人体血清地高辛浓度升高,其[I] / IC(50)值足够高,表明地高辛与替米沙坦之间的DDI是通过抑制肠道P-gp释放地高辛引起的。

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