Pharmacokinetic study of the hepatobiliary transport of indomethacin.
OBJECTIVE
The biliary excreted amount of indomethacin and its glucuronide is related to the intestinal toxicity of this drug. In the present study, we investigated the hepatobiliary transport of indomethacin.


METHODS
The uptake of indomethacin into primary cultured rat hepatocytes and COS-7 cells transfected with cDNA encoding sodium taurocholate co-transporting polypeptide or organic anion transporting polypeptide 1 was examined. Moreover, we compared the biliary excretion of indomethacin and its glucuronide between Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR) whose canalicular multispecific organic anion transporter/multidrug resistance associated protein 2 (cMOAT/MRP2) function is hereditarily defective.


RESULTS
The uptake of indomethacin into rat hepatocytes was mediated by Na+-dependent and independent active transport systems. Neither transfectant stimulated the uptake of indomethacin. After intravenous infusion of indomethacin to SD rats, the biliary excretion of indomethacin glucuronide exceeded that of indomethacin. The indomethacin transport clearance across the bile canalicular membrane was comparable between SD rats and EHBR, whereas the corresponding value for indomethacin glucuronide in EHBR was approximately 50% that in SD rats.


CONCLUSIONS
These results indicate that another transporter(s) is involved in the hepatic uptake of indomethacin and the canalicular transport of indomethacin glucuronide is mediated by cMOAT/MRP2 whereas that of indomethacin is not mediated by cMOAT/MRP2.
Kouzuki
H
H
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
Suzuki
H
H
Sugiyama
Y
Y
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D001659:Biliary Tract / Q000166:cytology / Q000378:metabolism*; D019556:COS Cells; D007213:Indomethacin / Q000493:pharmacokinetics*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012964:Sodium; D007213:Indomethacin