PT  - JOURNAL ARTICLE
AU  - Laurent Salphati
AU  - Xiaoyan Chu
AU  - Liangfu Chen
AU  - Bhagwat Prasad
AU  - Shannon Dallas
AU  - Raymond Evers
AU  - Donna Mamaril-Fishman
AU  - Ethan G. Geier
AU  - Jonathan Kehler
AU  - Jeevan Kunta
AU  - Mario Mezler
AU  - Loic Laplanche
AU  - Jodie Pang
AU  - Anja Rode
AU  - Matthew G. Soars
AU  - Jashvant D. Unadkat
AU  - Robert A. B. van Waterschoot
AU  - Jocelyn Yabut
AU  - Alfred H. Schinkel
AU  - Nico Scheer
TI  - Evaluation of Organic Anion Transporting Polypeptide 1B1 and 1B3 Humanized Mice as a Translational Model to Study the Pharmacokinetics of Statins
AID  - 10.1124/dmd.114.057976
DP  - 2014 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 1301--1313
VI  - 42
IP  - 8
4099  - http://dmd.aspetjournals.org/content/42/8/1301.short
4100  - http://dmd.aspetjournals.org/content/42/8/1301.full
SO  - Drug Metab Dispos2014 Aug 01; 42
AB  - 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. 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 liquid chromatography–tandem mass spectrometry, and 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 with Oatp1a/1b knockout controls under the conditions used in our studies. Hence, although 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 humans.