Pharmacokinetic Study of the Hepatobiliary Transport of Indomethacin |
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Authors: | Kouzuki Hirokazu Suzuki Hiroshi Sugiyama Yuichi |
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Institution: | (1) Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan;(2) Japan Science and Technology Corporation, Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan;(3) Japan Science and Technology Corporation, Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan |
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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. |
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Keywords: | indomethacin hepatic uptake Ntcp oatp biliary excretion cMOAT/MRP2 |
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