Construction Of Slco1b2 Gene Knockout Rat Model And Its Application In Pharmacokinetics

Organic anion transport polypeptides 1B1/3(OATP1B1/3)are important uptake transporters in humans.They play a fundamental role in the dynamic balance of endogenous substances and the pharmacodynamics of exogenous drugs.Oatp1b2,which is homologous to OATP1B1/3,is encoded by Slco1b2(Solute Carrier)in rats.gene.In order to study the function of OATP1B1/3 scientifically,Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)/CRISPR-associated protein-9nuclease(Cas9)system was applied to construct a novel Slco1b2 gene knockout rat model.Knockout(KO)rats could grow,develop and reproduce normally.The expression and function of Oatp1b2 were absent in KO rats,and no off-target and compensatory effects were detected.Serum total bilirubin and direct bilirubin were significantly increased in KO rats.In addition,the mechanism of drug-drug interaction(DDI)between paclitaxel and sorafenib was studied for the first time by using this model.In wild-type(WT)rats,sorafenib increased the systemic exposure and slowed the elimination of paclitaxel,resulting in DDI.However,in KO rats,the DDI disappeared.On the other hand,paclitaxel did not alter the pharmacokinetics profile of sorafenib in WT rats.The results showed that the DDI based on Oatp1b2 occurred when paclitaxel was jointly used with sorafenib.The results were further validated in vitro by overexpressing Oatp1b2 in cells.In summary,the Slco1b2 knockout rat model was innovatively constructed.This model can be used as a disease model of Rotor syndrome,as well as in the study of tumor biomarkers.At the same time,the model can be applied to pharmacokinetics studies,especially providing a powerful tool for drug research and development,DDI prediction and so on.In particular,this model was used to determine that Oatp1b2-mediated DDI between paclitaxel and sorafenib,which can provide a scientific reference for clinical safety of medication.