Abstract
A frequent limiting side-effect of irinotecan, CPT-11, is its gastrointestinal toxicity (diarrhea) thought to be related to the biliary excretion of CPT-11 and its metabolites. Accordingly, we have investigated their biliary excretion mechanism. Our in vivo pharmacokinetic studies in rats revealed that the biliary excretion clearance of the four anionic forms of CPT-11 and its metabolites ways much lower in Eisai hyperbilirubinemic rats (EHBR) with a genetic deficiency of the hepatic canalicular multispecific organic anion transporter (cMOAT). Detailed analysis using isolated liver bile canalicular membrane vesicles led to identify the multiplicity of transport systems. Such multiple primary active transport systems are also responsible for the biliary excretion of CPT-11 and its metabolites in humans, and the major transport systemforOPT-11 differs fromthat forthe othertwo compounds. Greater degree of inter-CMV variability in the uptake of SN-38 and SN38-Glu may imply that interindividual variability in their biliary excretion might contribute to the interpatient variability in the toxicity caused by CPT-11.
