Hepatic extraction, metabolism, and biliary excretion of irinotecan in theisolated perfused rat liver

Irinotecan (CPT-11) is a semisynthetic derivative of camptothecine that has proved activity in the treatment of colorectal carcinoma. The metabolites identified in humans include SN-38, SN-38 glucuronide, and several CYP3A-de rived metabolites. We have studied the hepatic extraction, metabolism, and biliary excretion of irinotecan in the isolated perfused rat liver. After i njection of a bolus dose of 5 mu mol in the reservoir, irinotecan lactone d isappeared from the perfusate following a two-exponential decay with half-l ives of 3.5 and 120 min and a total clearance of 1.54 +/- 0.07 mL/min per g ram of liver. The area under the curve (AUC) ratio lactone/total drug was 0 .212 +/- 0.098 and the half-life of interconversion was 5.02 +/- 0.10 min. Bolus administrations of 2.5, 5, and 25 mu mol of irinotecan gave AUCs prop ortional to the doses administered, indicating that no saturation occurred during dose increase. However, the relative formation of SN-38 and SN-38 gl ucuronide decreased at the high dose. This result was not the case for the CYP3A metabolites, which had identical metabolic ratios at all three doses. Infusions of 30 and 90 min of a dose of 5 mu mol led to the same AUCs and metabolic ratios as a bolus of the same dose. Biliary elimination of irinot ecan and metabolites represented 18-22% of the dose administered at 2.5 and 5 mu mol but only 7-9% at 25 mu mol, suggesting a saturation of this proce ss. These data indicate that the hepatic disposition of irinotecan may vary at high dose, both at the level of biliary excretion and of activation to SN-38. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Associatio n J Pharm Sci 90:722-731, 2001.