Construction and characterization of a humanized SLCO1B1 rat model with its application in evaluating the uptake of different statins  

作　　者：Yuanjin Zhang Junze Huang Shengbo Huang Jie Liu Luyao Deng Chenmeizi Liang Yuanqing Guo Bingyi Yao Xin Wang 

机构地区：[1]Changning Maternity and Infant Health Hospital and School of Life Sciences,Shanghai Key Laboratory of Regulatory Biology,East China Normal University,Shanghai 200241,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第4期1592-1604,共13页药学学报（英文版）

基　　金：This work was supported by grants from the National Natural Science Foundation of China(82274010);the Science and Technology Commission of Shanghai Municipality(18430760400,China);the East China Normal University(ECNU)Medicine and Health Joint Fund(2022JKXYD09004,China);the Jointed PI Program from Shanghai Changning Maternity and Infant Health Hospital;ECNU Construction Fund of Innovation and Entrepreneurship Laboratory.

摘　　要：Organic anion-transporting polypeptides IB1(OATPIB1)plays a crucial role in the transport of statins.However,there are too few animal models related to OATPIB1,especially humanized animal models.In this study,the human SLCOIB1 cDNA was inserted into the second exon of the rat Slcolb2 gene using CRISPR/Cas9 technology.Pharmacokinetic characteristics of statins were conducted in wild-type(WT),humanized OATPIB1(hOATPIB1),and OATPIB2 knockout(OATPIB2 KO)rats,respec-tively.The results showed that human OATPIB1 was successfully expressed in rat liver and exhibited transport function.Furthermore,the pharmacokinetic results revealed that OATPIB1 exhibited varying uptake levels of pivastatin,rosuvastatin,and fluvastatin,leading to different levels of exposure within the body.These results were consistent with those obtained from in vitro experiments using overexpressed cell lines.In conclusion,we established a novel humanized SLCOIBI transgenic rat model to assess the role of human OATPIB1 in the uptake of different statins.The different uptake mediated by OATPIB1 may be an important reason for the different efficacy of statins.The hOATPIB1 rat is a promising model for improving the prediction of human drug transport.

关 键 词：CRISPR/Cas9 Drug transport Drug disposition Geneediting Humanized rat model OATP1B1 SLCO1B1 STATINS 

分 类 号：R758.63[医药卫生—皮肤病学与性病学]