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Research ArticleArticle

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

J. William Higgins, Jing Q. Bao, Alice B. Ke, Jason R. Manro, John K. Fallon, Philip C. Smith and Maciej J. Zamek-Gliszczynski
Drug Metabolism and Disposition January 2014, 42 (1) 182-192; DOI: https://doi.org/10.1124/dmd.113.054783
J. William Higgins
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.)
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Jing Q. Bao
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.)
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Alice B. Ke
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.)
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Jason R. Manro
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.)
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John K. Fallon
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.)
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Philip C. Smith
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.)
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Maciej J. Zamek-Gliszczynski
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.)
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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).

Footnotes

    • Received September 9, 2013.
    • Accepted November 5, 2013.
  • dx.doi.org/10.1124/dmd.113.054783.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (1)
Drug Metabolism and Disposition
Vol. 42, Issue 1
1 Jan 2014
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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
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Research ArticleArticle

OATP in Drug Pharmacokinetics and Tissue Distribution

J. William Higgins, Jing Q. Bao, Alice B. Ke, Jason R. Manro, John K. Fallon, Philip C. Smith and Maciej J. Zamek-Gliszczynski
Drug Metabolism and Disposition January 1, 2014, 42 (1) 182-192; DOI: https://doi.org/10.1124/dmd.113.054783

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Research ArticleArticle

OATP in Drug Pharmacokinetics and Tissue Distribution

J. William Higgins, Jing Q. Bao, Alice B. Ke, Jason R. Manro, John K. Fallon, Philip C. Smith and Maciej J. Zamek-Gliszczynski
Drug Metabolism and Disposition January 1, 2014, 42 (1) 182-192; DOI: https://doi.org/10.1124/dmd.113.054783
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