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

• DOI: 10.1124/dmd.113.054783
• Publication Date: 2013-11-06T03:16:15Z
• Authors: J. William Higgins; Jing Q Bao; Alice B Ke; Jason R Manro; John K Fallon; Philip C Smith; Maciej J Zamek-Gl...
• Keywords: Knockout mouse; Humanized mouse; Gene knockout

Although organic anion transporting polypeptide (OATP)–mediated hepatic uptake is generally conserved between rodents and humans at a gross pharmacokinetic level, the presence of three major OATPs with broad overlap in substrate inhibitor affinity, absence rodent-human orthologs preclude clinical translation single-gene knockout/knockin findings. At present, changes pharmacokinetics tissue distribution pravastatin, atorvastatin, simvastatin, carboxydichlorofluorescein were studied oatp1a/1b-knockout mice lacking oatp isoforms, knockout liver-specific knockin human OATP1B1 or OATP1B3. Relative to wild-type controls, exhibited 1.6- 19-fold increased intravenous 2.1- 115-fold oral drug exposure, due 33%–75% decreased clearance, 14%–60% volume distribution, ≤74-fold bioavailability, magnitude change depending on contribution oatp1a/1b pharmacokinetics. Hepatic was 4.2- 196-fold lower mice; distributional attenuation less notable kidney, brain, cardiac, skeletal muscle. Knockin OATP1B3 partially restored control volume, bioavailability values (24%–142% increase, ≤47% ≤77% decrease vs. knockout, respectively), such that profiles positioned mice. Consistent humanization, only (1.3- 6.5-fold increase knockout). Exposure liver OATP1B1-humanized versus predicted impact exposure statins within 1.7-fold, but after correcting for human/humanized mouse relative protein expression factor (OATP1B1 = 2.2, 0.30).