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Research ArticleMetabolism, Transport, and Pharmacogenomics

Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans

Takao Watanabe, Hiroyuki Kusuhara, Kazuya Maeda, Yoshihisa Shitara and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 2009, 328 (2) 652-662; DOI: https://doi.org/10.1124/jpet.108.146647
Takao Watanabe
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Hiroyuki Kusuhara
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Kazuya Maeda
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Yoshihisa Shitara
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Yuichi Sugiyama
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This article has a correction. Please see:

  • Correction to “Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans” - May 01, 2011

Abstract

Hepatobiliary excretion mediated by transporters, organic anion-transporting polypeptide (OATP) 1B1 and multidrug resistance-associated protein (MRP) 2, is the major elimination pathway of an HMG-CoA reductase inhibitor, pravastatin. The present study examined the effects of changes in the transporter activities on the systemic and liver exposure of pravastatin using a physiologically based pharmacokinetic model. Scaling factors, determined by comparing in vivo and in vitro parameters of pravastatin in rats for the hepatic uptake and canalicular efflux, were obtained. The simulated plasma and liver concentrations and biliary excretion profiles were very close to the observed data in rats under linear and nonlinear conditions. In vitro parameters, determined in human cryopreserved hepatocytes and canalicular membrane vesicles, were extrapolated to in vivo parameters using the scaling factors obtained in rats. The simulated plasma concentrations of pravastatin were close to the reported values in humans. Sensitivity analyses showed that changes in the hepatic uptake ability altered the plasma concentration of pravastatin markedly but had a minimal effect on the liver concentration, whereas changes in the ability of canalicular efflux altered the liver concentration of pravastatin markedly but had a small effect on the plasma concentration. In conclusion, the model allows the prediction of the disposition of pravastatin in humans. The present study suggests that changes in the OATP1B1 activities may have a small and a large impact on the therapeutic efficacy and side effect (myopathy) of pravastatin, respectively, whereas those in the MRP2 activities may have opposite impacts (i.e., large and small impacts on the therapeutic efficacy and side effect).

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi;10.1124/jpet.108.146647.

  • ABBREVIATIONS:

    CMV
    canalicular membrane vesicle
    PBPK
    physiologically based pharmacokinetic
    OATP
    organic anion-transporting polypeptide
    MRP
    multidrug resistance-associated protein
    SF
    scaling factor
    R-122798
    (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-8-(isobutyryloxy)-2-methyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]heptanoic acid
    LC/MS
    liquid chromatography/mass spectrometry
    PS
    permeability surface product
    inf
    influx
    dif
    diffusion
    CL
    clearance
    met
    metabolism
    tot
    total
    B
    blood
    AUC
    area(s) under the concentration-time curve.

  • Received September 25, 2008.
  • Accepted November 7, 2008.
  • Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 3
1 Jun 2023
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans

Takao Watanabe, Hiroyuki Kusuhara, Kazuya Maeda, Yoshihisa Shitara and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 652-662; DOI: https://doi.org/10.1124/jpet.108.146647

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans

Takao Watanabe, Hiroyuki Kusuhara, Kazuya Maeda, Yoshihisa Shitara and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 652-662; DOI: https://doi.org/10.1124/jpet.108.146647
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