Hepatic transport, metabolism and biliary excretion of irinotecan in a cancer patient with an external bile drain.

摘要

BACKGROUND: Irinotecan is metabolized by various enzymes, including carboxylesterases, cytochrome P450 3A isozymes (CYP3A) and uridine-diphosphate glucuronosyltransferase 1A isoforms (UGT1A). Here we report on the disposition of irinotecan and its metabolites in plasma, urine, bile and feces of a single cancer patient with an external bile drain. METHODOLOGY: Irinotecan (450 mg) was administered during a 90-minutes continuous infusion to a cancer patient with an external bile drain. Blood samples were collected up to 55 hours after infusion, while bile, feces and urine were collected during six consecutive days after administration. Samples were analyzed using high-performance liquid chromatography (HPLC)-assays with fluorescence detection. RESULTS: Plasma pharmacokinetics were characterized by a relatively slow clearance of irinotecan and a relatively high exposure to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC). Exposures to the other metabolites was within the normal range. Overall, 83.4% of the administered dose was recovered in the excreta, with the majority excreted during the first 24 hours. CONCLUSIONS: Enterohepatic recirculation is of minor importance for the plasma disposition of irinotecan and its metabolites. The high percentage of the dose recovered in urine, the relatively slow clearance of irinotecan and the preferential urinary over biliary excretion of APC in this particular patient are likely related to reduced functioning of ABC-transporters. Circumstantial evidence was found that APC is subject to further intestinal biotransformation indicating a role in the etiology of irinotecan-induced diarrhea. Since intra-luminal exposure to SN-38 in patients with an external bile drain is limited, neutropenia will be the dose-limiting toxicity. Based on presented data, although collected from only one patient, irinotecan therapy in patients with an external bile drain is feasible. No a priori dose adjustments are recommended, although in the absence of severe side-effects in previous courses, a higher dose may be considered.