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

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.

CRISPR-Cas9: A method for establishing rat models of drug metabolism and pharmacokinetics

The 2020 Nobel Prize in Chemistry recognized CRISPR-Cas9,a super-selective and precise gene editing tool.CRISPR-Cas9 has an obvious advantage in editing multiple genes in the same cell,and presents great potential in disease treatment and animal model construction.In recent years,CRISPRCas9 has been used to establish a series of rat models of drug metabolism and pharmacokinetics(DMPK),such as Cyp,Abcb1,Oatp1 b2 gene knockout rats.These new rat models are not only widely used in the study of drug metabolism,chemical toxicity,and carcinogenicity,but also promote the study of DMPK related mechanism,and further strengthen the relationship between drug metabolism and pharmacology/toxicology.This review systematically introduces the advantages and disadvantages of CRISPR-Cas9,summarizes the methods of establishing DMPK rat models,discusses the main challenges in this field,and proposes strategies to overcome these problems.