OAT1 and OAT3: Targets of drug-drug interaction between entecavir and JBP485
OAT1 and OAT3: Targets of drug-drug interaction between entecavir and JBP485
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OAT1和OAT3：恩替卡韦和JBP485之间药物相互作用的靶点
DOI：
10.1016/j.ejps.2012.12.024
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发表时间：
2013-03-12
影响因子：
4.6
通讯作者：
Liu, Kexin
中科院分区：
文献类型：
--
作者：
Xu, Qinghan;Wang, Changyuan;Liu, Kexin
恩替卡韦和二肽JBP 485具有抗肝炎活性，两药合用治疗肝炎是可能的。我们的目的是阐明恩替卡韦是否是OAT 1，OAT 3，OCT和PEPT 1的底物，并研究恩替卡韦和JBP 485之间的药物相互作用的靶点。采用LC-MS/MS法测定了大鼠体内静脉和口服恩替卡韦后血浆和尿液中的浓度，以及体外肾切片和转染细胞对恩替卡韦的摄取。大鼠静脉联合给予恩替卡韦和JBP 485后，恩替卡韦的AUC增加了1.93倍，而JBP 485的AUC增加了1.93倍。（1/2 β）延长2.08倍，CLP降低49%，肌酐降低73%，累积尿排泄量降低54%。然而，口服联合给药后，恩替卡韦Tmax和C-max未受影响;其他药代动力学参数（AUC、t（1/2 β）、CLP和累积尿排泄）的变化程度与静脉给药相似。恩替卡韦的摄取在hPEPT 1-中与在载体-HELA细胞中几乎相同。在大鼠肾切片中，恩替卡韦的摄取被对氨基马尿酸盐、苄青霉素、JBP 485和四乙基铵显著抑制。在hOAT 1-和hOAT 3-HEK 293细胞中，恩替卡韦的摄取显著高于载体-HEK 293细胞，并受到对氨基马尿酸盐、苄青霉素和JBP 485的显著抑制。恩替卡韦的Km和Vmax值分别为250 μ M和0.83 nmol/mg蛋白/30 s（OAT 1）和23 μ M和1.1 nmol/mg蛋白/30 s（OAT 3）。恩替卡韦是OAT 1、OAT 3和OCT的底物，而且OAT 1和OAT 3是恩替卡韦与JBP 485之间DDI的靶点。(C)2013爱思唯尔有限公司版权所有。
Entecavir and JBP485 (a dipeptide) exhibit the antihepatitis activities and it is possible for the two drugs to be coadministered in the treatment of hepatitis. We aimed to elucidate whether entecavir was a substrate of OAT1, OAT3, OCT, and PEPT1 and to investigate the targets of drug-drug interactions between entecavir and JBP485. Plasma and urine concentrations of entecavir following intravenous and oral administration in vivo, uptake of entecavir in kidney slices and transfected cells in vitro, were determined by LC-MS/MS. Following intravenous co-administration of entecavir and JBP485 in rats, entecavir AUC increased 1.93-fold, t(1/2 beta) was prolonged 2.08-fold, CLP decreased 49%, CLR decreased 73%, and accumulated urinary excretion decreased 54%. However, following oral co-administration, the entecavir T-max and C-max were not affected; the degree of change in other pharmacokinetic parameters (AUC, t(1/2 beta), CLP, and accumulated urinary excretion) was similar to that of intravenous administration. The uptake of entecavir was nearly identical in hPEPT1- as in vector-HELA cells. In rat kidney slices, uptake of entecavir was markedly inhibited by p-aminohippurate, benzylpenicillin, JBP485, and tetraethyl ammonium. In hOAT1- and hOAT3-HEK293 cells, uptake of entecavir was significantly higher compared to vector-HEK293 cells and was markedly inhibited by p-aminohippurate, benzylpenicillin, and JBP485. Km and Vmax values of entecavir were 250 mu M and 0.83 nmol/mg protein/30 s (OAT1) and 23 mu M and 1.1 nmol/mg protein/30 s (OAT3), respectively. Entecavir is the substrate of OAT1, OAT3, and OCT. Moreover, OAT1 and OAT3 are the targets of DDI between entecavir and JBP485. (C) 2013 Elsevier B.V. All rights reserved.