@article {Higgins182, author = {J. William Higgins and Jing Q. Bao and Alice B. Ke and Jason R. Manro and John K. Fallon and Philip C. Smith and Maciej J. Zamek-Gliszczynski}, title = {Utility of Oatp1a/1b-Knockout and OATP1B1/3-Humanized Mice in the Study of OATP-Mediated Pharmacokinetics and Tissue Distribution: Case Studies with Pravastatin, Atorvastatin, Simvastatin, and Carboxydichlorofluorescein}, volume = {42}, number = {1}, pages = {182--192}, year = {2014}, doi = {10.1124/dmd.113.054783}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Although organic anion transporting polypeptide (OATP){\textendash}mediated hepatic uptake is generally conserved between rodents and humans at a gross pharmacokinetic level, the presence of three major hepatic OATPs with broad overlap in substrate and inhibitor affinity, and absence of rodent-human orthologs preclude clinical translation of single-gene knockout/knockin findings. At present, changes in pharmacokinetics and tissue distribution of pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein were studied in oatp1a/1b-knockout mice lacking the three major hepatic oatp isoforms, and in knockout mice with liver-specific knockin of human OATP1B1 or OATP1B3. Relative to wild-type controls, oatp1a/1b-knockout mice exhibited 1.6- to 19-fold increased intravenous and 2.1- to 115-fold increased oral drug exposure, due to 33\%{\textendash}75\% decreased clearance, 14\%{\textendash}60\% decreased volume of distribution, and <=74-fold increased oral bioavailability, with the magnitude of change depending on the contribution of oatp1a/1b to pharmacokinetics. Hepatic drug distribution was 4.2- to 196-fold lower in oatp1a/1b-knockout mice; distributional attenuation was less notable in kidney, brain, cardiac, and skeletal muscle. Knockin of OATP1B1 or OATP1B3 partially restored control clearance, volume, and bioavailability values (24\%{\textendash}142\% increase, <=47\% increase, and <=77\% decrease vs. knockout, respectively), such that knockin pharmacokinetic profiles were positioned between knockout and wild-type mice. Consistent with liver-specific humanization, only hepatic drug distribution was partially restored (1.3- to 6.5-fold increase vs. knockout). Exposure and liver distribution changes in OATP1B1-humanized versus knockout mice predicted the clinical impact of OATP1B1 on oral exposure and contribution to human hepatic uptake of statins within 1.7-fold, but only after correcting for human/humanized mouse liver relative protein expression factor (OATP1B1 = 2.2, OATP1B3 = 0.30).}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/42/1/182}, eprint = {https://dmd.aspetjournals.org/content/42/1/182.full.pdf}, journal = {Drug Metabolism and Disposition} }