Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats.
Irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11), is a potent anticancer drug that is increasingly used in chemotherapy. A frequent limiting side effect involves gastrointestinal toxicity (diarrhea), which is thought to be related to the biliary excretion of CPT-11 and its metabolites. Accordingly, the biliary excretion mechanisms for both the lactone and carboxylate forms of CPT-11 and its metabolites, SN-38 and its glucuronide (SN38-Glu), were investigated using Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR), with the latter being mutant rats with a genetic deficiency of the canalicular multispecific organic anion transporter. After i.v. administration of CPT-11, the biliary excretion clearance, defined as the biliary excretion rate normalized to the hepatic concentration, of both the lactone and carboxylate forms of SN38-Glu was much lower in EHBR. The biliary excretion clearance for the carboxylate form of both CPT-11 and SN-38 was also substantially smaller in EHBR and showed marked saturation with increasing dose only in SD rats. On the other hand, the biliary excretion clearance for the lactone forms of CPT-11 and SN-38 showed only a minimal difference in EHBR, compared with SD rats. These results suggest that, for the carboxylate form of CPT-11 and SN-38 and the carboxylate and lactone forms of SN38-Glu, there exists a specific transport system at the bile canalicular membrane that is deficient in EHBR. To confirm this hypothesis, the uptake of these substrates by isolated hepatic canalicular membrane vesicles (CMV) was examined. ATP-dependence was clearly observed for the uptake of these four compounds by CMV prepared from SD rats but not by CMV from EHBR. In addition, the compounds inhibited the ATP-dependent uptake of S-(2,4-dinitrophenyl) glutathione by CMV from SD rats, in a concentration-dependent manner. These results suggest that the biliary excretion of the carboxylate forms of CPT-11 and SN-38 and the carboxylate and lactone forms of SN38-Glu is mediated by the multispecific organic anion transporter, which is deficient in EHBR.
Chu
X Y
XY
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Kato
Y
Y
Niinuma
K
K
Sudo
K I
KI
Hakusui
H
H
Sugiyama
Y
Y
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D027321:Anion Transport Proteins; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001646:Bile / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D006932:Hyperbilirubinemia / Q000378:metabolism; D000077146:Irinotecan; D008297:Male; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley
D027321:Anion Transport Proteins; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; C106003:SN38-Glu; D000077146:Irinotecan; D000255:Adenosine Triphosphate; D002166:Camptothecin