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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Inhibition of Biliary Excretion of Methotrexate by Probenecid in Rats: Quantitative Prediction of Interaction from in Vitro Data

Kaoru Ueda, Yukio Kato, Kanji Komatsu and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics June 2001, 297 (3) 1036-1043;
Kaoru Ueda
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Yukio Kato
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Kanji Komatsu
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Yuichi Sugiyama
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Abstract

This study was designed to establish a strategy to predict drug interactions involving biliary excretion. The interaction between methotrexate and probenecid was examined as an interaction model since this interaction has already been clinically reported. Coadministration of probenecid reduced the biliary clearance of methotrexate in a dose-dependent manner in rats. This inhibition by probenecid was confirmed in vivo both in the uptake and excretion processes of methotrexate across sinusoidal and canalicular membranes, respectively. That is, both hepatic uptake clearance, assessed in integration plot analysis, and steady-state biliary clearance defined with respect to hepatic unbound methotrexate, were reduced in the presence of probenecid. Probenecid inhibited the active transport of methotrexate both in isolated hepatocytes and canalicular membrane vesicles, confirming the interaction at those two membranes. The degree of inhibition of the uptake and excretion processes found in vivo was comparable with the predicted values using the inhibition constant assessed in isolated hepatocytes and canalicular membranes, respectively. This suggests that the interaction at each membrane transport process can be quantitatively estimated from in vitro data. We have also proposed the method to predict the degree of inhibition of the net excretion from circulating plasma into the bile, the predicted values being also comparable with the inhibition actually found in vivo. The present analysis demonstrates a strategic rationale for predicting drug interactions involving biliary excretion using in vitro systems to avoid any false negative predictions.

Footnotes

  • Send reprint requests to: Professor Yuichi Sugiyama, Ph.D., Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033. E-mail:BXG05433{at}nifty.ne.jp

  • This study was supported in part by a grant-in-aid for Scientific Research provided by the Ministry of Education, Science and Culture of Japan.

  • Abbreviations:
    CMV
    canalicular membrane vesicle
    HPLC
    high-performance liquid chromatography
    fp
    free fraction in plasma
    fh
    free fraction in liver
    CLtotal
    total body clearance
    CLbile,p
    biliary clearance with respect to circulating plasma
    CLbile,h
    biliary clearance with respect to the liver concentration
    Cpss
    steady-state plasma concentration
    Chss
    steady-state liver concentration
    Vbile
    biliary excretion rate
    CLint,bile
    intrinsic clearance for net biliary excretion
    P1
    intrinsic clearance for hepatic uptake
    P2
    intrinsic clearance for the sinusoidal efflux
    P3
    intrinsic clearance for biliary excretion across canalicular membrane
    Qp
    hepatic plasma flow rate
    Xliver
    the amount of drug in the liver
    AUC
    area under the curve
    Iu,plasma
    unbound inhibitor concentration in plasma
    Iu,liver
    unbound inhibitor concentration in liver
    Rb
    blood-to-plasma concentration ratio
    cMOAT/MRP2
    canalicular multispecific organic anion transporter/multiresistance protein 2
    • Received November 21, 2000.
    • Accepted February 7, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 297 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 3
1 Jun 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Inhibition of Biliary Excretion of Methotrexate by Probenecid in Rats: Quantitative Prediction of Interaction from in Vitro Data

Kaoru Ueda, Yukio Kato, Kanji Komatsu and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 1036-1043;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Inhibition of Biliary Excretion of Methotrexate by Probenecid in Rats: Quantitative Prediction of Interaction from in Vitro Data

Kaoru Ueda, Yukio Kato, Kanji Komatsu and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 1036-1043;
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