Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.
Eur J Pharm Sci. 2013 Mar 12;48(4-5):650-7. doi: 10.1016/j.ejps.2012.12.024. Epub 2013 Jan 9.
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, t1/2β was prolonged 2.08-fold, CLP decreased 49%, CLR decreased 73%, and accumulated urinary excretion decreased 54%. However, following oral co-administration, the entecavir Tmax and Cmax were not affected; the degree of change in other pharmacokinetic parameters (AUC, t1/2β, 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 μM and 0.83 nmol/mg protein/30s (OAT1) and 23 μM 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.
恩替卡韦和 JBP485（二肽）具有抗肝炎活性，这两种药物有可能联合用于治疗肝炎。我们旨在阐明恩替卡韦是否为 OAT1、OAT3、OCT 和 PEPT1 的底物，并研究恩替卡韦与 JBP485 之间药物相互作用的靶点。通过 LC-MS/MS 测定体内静脉和口服给药后恩替卡韦的血浆和尿液浓度、体外肾切片和转染细胞摄取恩替卡韦。在大鼠中静脉联合给予恩替卡韦和 JBP485 后，恩替卡韦 AUC 增加 1.93 倍，t1/2β 延长 2.08 倍，CLP 降低 49%，CLR 降低 73%，累积尿排泄减少 54%。然而，口服联合给药后，恩替卡韦的 Tmax 和 Cmax 不受影响；其他药代动力学参数（AUC、t1/2β、CLP 和累积尿排泄）的变化程度与静脉给药相似。hPEPT1-和载体-HELA 细胞摄取恩替卡韦几乎相同。在大鼠肾切片中，恩替卡韦的摄取被对氨基马尿酸、青霉素 G、JBP485 和四乙铵显著抑制。在 hOAT1-和 hOAT3-HEK293 细胞中，与载体-HEK293 细胞相比，恩替卡韦的摄取显著增加，并且被对氨基马尿酸、青霉素 G 和 JBP485 显著抑制。恩替卡韦的 Km 和 Vmax 值分别为 250 μM 和 0.83 nmol/mg 蛋白/30s（OAT1）和 23 μM 和 1.1 nmol/mg 蛋白/30 s（OAT3）。恩替卡韦是 OAT1、OAT3 和 OCT 的底物。此外，OAT1 和 OAT3 是恩替卡韦与 JBP485 之间 DDI 的靶点。
