Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.
Eur J Pharm Sci. 2012 Sep 29;47(2):341-6. doi: 10.1016/j.ejps.2012.06.004. Epub 2012 Jun 21.
The purpose is to investigate whether the targets of drug-drug interactions (DDIs) between JBP485 and acyclovir are OAT1 and OAT3 in kidney. Plasma concentration and accumulative urinary excretion of acyclovir in vivo, uptake of acyclovir in kidney slices and uptake of acyclovir in human (h) OAT1/ hOAT3-human embryonic kidney (HEK) 293 cells in vitro were performed to examine the effect of JBP485 on urinary excretion of acyclovir. The plasma concentration of acyclovir was increased markedly and accumulative urinary excretion and renal clearance of acyclovir were decreased significantly after intravenous administration of acyclovir in combination with JBP485. JBP485 (a substrate for OAT1 and OAT3), p-aminohippurate (PAH) (a substrate for OAT1) and benzylpenicillin (PCG) (a substrate for OAT3) could decrease the uptake of acyclovir in kidney slices and in hOAT1-/hOAT3-HEK293 cells. These results suggest that JBP485 inhibits the renal excretion of acyclovir by inhibiting renal transporters OAT1 and OAT3 in vivo and in vitro. Our results indicate the possibility of DDI between dipeptide and acyclovir.
目的在于研究 JBP485 与阿昔洛韦之间的药物相互作用（DDI）的作用靶点是否为肾脏中的 OAT1 和 OAT3。通过体内研究阿昔洛韦的血浆浓度和累积尿排泄、肾切片摄取阿昔洛韦以及人（h）OAT1/hOAT3-人胚肾（HEK）293 细胞摄取阿昔洛韦，来检测 JBP485 对阿昔洛韦尿排泄的影响。静脉注射阿昔洛韦联合 JBP485 后，阿昔洛韦的血浆浓度显著增加，累积尿排泄和肾清除率明显降低。JBP485（OAT1 和 OAT3 的底物）、对氨马尿酸（PAH）（OAT1 的底物）和苯唑西林（PCG）（OAT3 的底物）可降低肾切片和 hOAT1-/hOAT3-HEK293 细胞中阿昔洛韦的摄取。这些结果表明，JBP485 可通过体内和体外抑制肾脏转运蛋白 OAT1 和 OAT3 来抑制阿昔洛韦的肾脏排泄。我们的研究结果表明二肽与阿昔洛韦之间存在药物相互作用的可能性。
