Abstract
Organic anion transporting polypeptide (Oatp) 1a/1b knockout and OATP1B1 and -1B3 humanized mouse models are promising tools for studying the roles of these transporters in drug disposition. Detailed characterization of these models will help to better understand their utility for predicting clinical outcomes. In order to advance this approach, we carried out a comprehensive analysis of these mouse lines by evaluating the compensatory changes in mRNA expression, quantifying the amounts of OATP1B1 and -1B3 protein by LC-MS/MS, studying the active uptake in isolated hepatocytes and the pharmacokinetics of some prototypical substrates including statins. Major outcomes from these studies were (1) mostly moderate compensatory changes in only a few genes involved in drug metabolism and disposition, (2) a robust hepatic expression of OATP1B1 and -1B3 proteins in the respective humanized mouse models, and (3) functional activities of the human transporters in hepatocytes isolated from the humanized models with several substrates tested in vitro and with pravastatin in vivo. However, the expression of OATP1B1 and -1B3 in the humanized models did not significantly alter liver or plasma concentrations of rosuvastatin and pitavastatin compared to Oatp1a/1b knockout controls under the conditions employed in our studies. Hence, while the humanized OATP1B1 and -1B3 mice showed in vitro and /or in vivo functional activity with some statins, further characterization of these models is required to define their potential use and limitations in the prediction of drug disposition and drug-drug interactions in human.
- active transport
- drug disposition
- drug toxicity
- drug-drug interactions
- genetically modified animal models
- hepatic transport
- hepatic uptake
- in vitro-in vivo prediction (IVIVE)
- pharmacokinetics
- transgenic models
- The American Society for Pharmacology and Experimental Therapeutics