Pharmaceutical Research

, Volume 17, Issue 4, pp 432–438

Pharmacokinetic Study of the Hepatobiliary Transport of Indomethacin

  • Hirokazu Kouzuki
  • Hiroshi Suzuki
  • Yuichi Sugiyama
Article

DOI: 10.1023/A:1007576903935

Cite this article as:
Kouzuki, H., Suzuki, H. & Sugiyama, Y. Pharm Res (2000) 17: 432. doi:10.1023/A:1007576903935

Abstract

Purpose. The biliary excreted amount of indomethacin and itsglucuronide is related to the intestinal toxicity of this drug. In the presentstudy, we investigated the hepatobiliary transport of indomethacin.Methods. The uptake of indomethacin into primary cultured rathepatocytes and COS-7 cells transfected with cDNA encoding sodiumtauro-cholate co-transporting polypeptide or organic anion transportingpolypeptide 1 was examined. Moreover, we compared the biliaryexcretion of indomethacin and its glucuronide between Sprague-Dawley(SD) rats and Eisai hyperbilirubinemic rats (EHBR) whose canalicularmultispecific organic anion transporter/multidrug resistance associatedprotein 2 (cMOAT/MRP2) function is hereditarily defective.Results. The uptake of indomethacin into rat hepatocytes was mediatedby Na+-dependent and independent active transport systems. Neithertransfectant stimulated the uptake of indomethacin. After intravenousinfusion of indomethacin to SD rats, the biliary excretion ofindomethacin glucuronide exceeded that of indomethacin. The indomethacintransport clearance across the bile canalicular membrane wascomparable between SD rats and EHBR, whereas the corresponding value forindomethacin glucuronide in EHBR was approximately 50% that inSD rats.Conclusions. These results indicate that another transporter(s) isinvolved in the hepatic uptake of indomethacin and the canaliculartransport of indomethacin glucuronide is mediated by cMOAT/MRP2whereas that of indomethacin is not mediated by cMOAT/MRP2.

indomethacin hepatic uptake Ntcp oatp biliary excretion cMOAT/MRP2 

Copyright information

© Plenum Publishing Corporation 2000

Authors and Affiliations

  • Hirokazu Kouzuki
    • 1
  • Hiroshi Suzuki
    • 1
    • 2
  • Yuichi Sugiyama
    • 1
    • 3
  1. 1.Graduate School of Pharmaceutical SciencesThe University of Tokyo, Hongo, Bunkyo-kuTokyoJapan
  2. 2.Japan Science and Technology Corporation, Hongo, Bunkyo-KuTokyoJapan
  3. 3.Japan Science and Technology Corporation, Hongo, Bunkyo-KuTokyoJapan

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