RT Journal Article
SR Electronic
T1 Evaluation of Organic Anion Transporting Polypeptide 1B1 and 1B3 Humanized Mice as a Translational Model to Study the Pharmacokinetics of Statins
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1301
OP 1313
DO 10.1124/dmd.114.057976
VO 42
IS 8
A1 Salphati, Laurent
A1 Chu, Xiaoyan
A1 Chen, Liangfu
A1 Prasad, Bhagwat
A1 Dallas, Shannon
A1 Evers, Raymond
A1 Mamaril-Fishman, Donna
A1 Geier, Ethan G.
A1 Kehler, Jonathan
A1 Kunta, Jeevan
A1 Mezler, Mario
A1 Laplanche, Loic
A1 Pang, Jodie
A1 Rode, Anja
A1 Soars, Matthew G.
A1 Unadkat, Jashvant D.
A1 van Waterschoot, Robert A. B.
A1 Yabut, Jocelyn
A1 Schinkel, Alfred H.
A1 Scheer, Nico
YR 2014
UL http://dmd.aspetjournals.org/content/42/8/1301.abstract
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.