Abstract
Although OATP-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 1.6-19 fold increased intravenous and 2.1-115 fold increased oral drug exposure, due to 33-75% decreased clearance, 14-60% 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 4.2-196 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 (24-142% increase, ≤47% increase, and ≤77% decrease versus 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 (1.3-6.5 fold increase versus 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 relative protein expression factor (OATP1B1 = 2.2, OATP1B3 = 0.30).
- blood-CNS transport
- drug disposition
- drug distribution
- drug interactions
- drug transport
- hepatic transport
- hepatic uptake
- organic anion transport
- pharmacokinetics
- renal transport
- The American Society for Pharmacology and Experimental Therapeutics