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

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

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Organic anion-transporting polypeptides 1B1(OATP1B1)plays a crucial role in the transport of statins.However,there are too few animal models related to OATP1B1,especially humanized animal models.In this study,the human SLCO1B1 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 OATP1B1(hOATP1B1),and OATP1B2 knockout(OATP1B2 KO)rats,respec-tively.The results showed that human OATP1B1 was successfully expressed in rat liver and exhibited transport function.Furthermore,the pharmacokinetic results revealed that OATP1B1 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 SLCO1B1 transgenic rat model to assess the role of human OATP1B1 in the uptake of different statins.The different uptake mediated by OATP1B1 may be an important reason for the different efficacy of statins.The hOATP1B1 rat is a promising model for improving the prediction of human drug transport.

CRISPR/Cas9Drug transportDrug dispositionGene editingHumanized rat modelOATP1B1SLCO1B1Statins

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

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Changning Maternity and Infant Health Hospital and School of Life Sciences,Shanghai Key Laboratory of Regulatory Biology,East China Normal University,Shanghai 200241,China

国家自然科学基金上海市科委项目East China Normal University(ECNU)Medicine and Health Joint Fund,ChinaJointed PI Program from Shanghai Changning Maternity and Infant Health HospitalECNU Construction Fund of Innovation and Entrepreneurship LaboratoryECNU multifunctional Platform for InnovationInstruments Sharing Platform of School of Life Sciences,East China Normal University(Shanghai,China)

82274010184307604002022JKXYD09004011

2024

10.1016/j.apsb.2023.12.019

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(4)
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