Pharmacokinetic study of the hepatobiliary transport of indomethacin

Purpose. 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 a nd COS-7 cells transfected with cDNA encoding sodium taurocholate co-transp orting polypeptide or organic anion transporting polypeptide 1 was examined . Moreover, we compared the biliary excretion of indomethacin and its glucu ronide between Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats ( EHBR) whose canalicular multispecific organic anion transporter/multidrug r esistance associated protein 2 (cMOAT/MRP2) function is hereditarily defect ive. Results. The uptake of indomethacin into rat hepatocytes was mediated by Na t-dependent and independent active transport systems. Neither transfectant stimulated the uptake of indomethacin. After intravenous infusion of indome thacin to SD rats, the biliary excretion of indomethacin glucuronide exceed ed that of indomethacin. The indomethacin transport clearance across the bi le canalicular membrane was comparable between SD rats and EHBR, whereas th e corresponding value for indomethacin glucuronide in EHBR was approximatel y 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 ind omethacin glucuronide is mediated by cMOAT/MRP2 whereas that of indomethaci n is not mediated by cMOAT/MRP2.