European Journal of Pharmaceutical Sciences 2015-04-25

Decreased liver distribution of entecavir is related to down-regulation of Oat2/Oct1 and up-regulation of Mrp1/2/3/5 in rat liver fibrosis.

Qinghan Xu, Changyuan Wang, Qi Liu, Qiang Meng, Huijun Sun, Jinyong Peng, Pengyuan Sun, Xiaokui Huo, Kexin Liu

Index: Eur. J. Pharm. Sci. 71 , 73-9, (2015)

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Abstract

We aimed to elucidate whether entecavir was taken-up into liver by transporters and clarify the possible molecular mechanisms of changes in the distribution of entecavir in rat liver fibrosis.Thioacetamide (TAA) was applied to induce rat liver fibrosis. Samples of liver uptake index (LUI) study and uptake of entecavir in isolated rat hepatocytes were determined by LC-MS/MS. qRT-PCR and western blotting were used to examine the expression of transporters in rat liver.The uptake of entecavir in hepatocytes was significantly higher at 37 °C compared to 4 °C. Furthermore, TEA and PAH could inhibit significantly the uptake of entecavir by the hepatocytes. It indicated that Oat2 and Oct1 were contributed to uptake of entecavir. Compared with control group, LUI and the uptake of entecavir, PAH and TEA in hepatocytes were significantly reduced in liver fibrosis group. Further study indicated that entecavir Vmax in liver fibrosis group was significantly decreased while the Km was not changed. These results indicated that transport capacity TAA treated isolated rat liver hepatocytes were reduced. Oat2 and Oct1 expressions were down-regulated and Mrp1/2/3/5 mRNA expressions were up-regulated in liver fibrosis group.The changes of these transporters were contributed to decrease liver distribution of entecavir.Copyright © 2015 Elsevier B.V. All rights reserved.