Multiplicity of biliary excretion mechanisms for the camptothecin derivative irinotecan (CPT-11), its metabolite SN-38, and its glucuronide: role of canalicular multispecific organic anion transporter and P-glycoprotein.
A frequent dose-limiting effect of irinotecan (CPT-11) is its gastrointestinal toxicity (diarrhea), which is thought to be related to biliary excretion of CPT-11 and its metabolites. Accordingly, we have investigated the mechanism of biliary excretion of these compounds. In vivo pharmacokinetic studies revealed that the biliary excretion of the four anionic forms of CPT-11 and its metabolites was reduced in Eisai hyperbilirubinemic rats, which carry a mutation of the hepatic canalicular multispecific organic anion transporter (cMOAT) gene. The protein encoded by this gene is expressed on the bile canalicular membrane and is responsible for the transport of organic anions into bile. Detailed analysis using isolated liver bile canalicular membrane vesicles to identify transport systems showed that cMOAT is responsible for biliary excretion of the low-affinity component of the carboxylate form of CPT-11 and the high-affinity component of both the lactone and carboxylate forms of SN-38 glucuronide. The carboxylate form of SN-38 is transported by cMOAT alone. Transport of the high-affinity component of CPT-11 was inhibited by verapamil and PSC-833, but their effect on the transport of its low-affinity component was minimal. In addition, ATP dependence in the uptake of CPT-11 by membrane vesicles obtained from a P-glycoprotein (P-gp)-overexpressing cell line was observed. Thus P-gp may be responsible for transport of the high-affinity component of the carboxylate form of CPT-11.
Sugiyama
Y
Y
Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
Kato
Y
Y
Chu
X
X
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D027321:Anion Transport Proteins; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000493:pharmacokinetics; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000378:metabolism*; D051381:Rats
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027321:Anion Transport Proteins; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D005965:Glucuronates; D000077146:Irinotecan; D002166:Camptothecin