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.
abstract: 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 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%-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- 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%-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).
authors.affiliation: Drug Disposition (J.W.H., J.Q.B., A.B.K., M.J.Z.-G.) and Global Statistical Sciences (J.R.M.), Lilly Research Laboratories, Indianapolis, Indiana; and Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S., M.J.Z.-G.).
authors.forename: J William
authors.initials: JW
authors.lastname: Higgins
authors.forename: Jing Q
authors.initials: JQ
authors.lastname: Bao
authors.forename: Alice B
authors.initials: AB
authors.lastname: Ke
authors.forename: Jason R
authors.initials: JR
authors.lastname: Manro
authors.forename: John K
authors.initials: JK
authors.lastname: Fallon
authors.forename: Philip C
authors.initials: PC
authors.lastname: Smith
authors.forename: Maciej J
authors.initials: MJ
authors.lastname: Zamek-Gliszczynski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000069059:Atorvastatin; D001682:Biological Availability; D006538:Heptanoic Acids / Q000493:pharmacokinetics*; D006801:Humans; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D017035:Pravastatin / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000493:pharmacokinetics*; D019821:Simvastatin / Q000493:pharmacokinetics*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014018:Tissue Distribution / Q000502:physiology; D055815:Young Adult
chemical_list: D006538:Heptanoic Acids; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D011758:Pyrroles; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000069059:Atorvastatin; D019821:Simvastatin; D017035:Pravastatin