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-derived metabolites. We have studied the hepatic extraction, metabolism, and biliary excretion of irinotecan in the isolated perfused rat liver. After injection of a bolus dose of 5 micromol in the reservoir, irinotecan lactone disappeared from the perfusate following a two-exponential decay with half-lives of 3.5 and 120 min and a total clearance of 1.54 +/- 0.07 mL/min per gram 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 micromol of irinotecan gave AUCs proportional to the doses administered, indicating that no saturation occurred during dose increase. However, the relative formation of SN-38 and SN-38 glucuronide 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 micromol led to the same AUCs and metabolic ratios as a bolus of the same dose. Biliary elimination of irinotecan and metabolites represented 18-22% of the dose administered at 2.5 and 5 micromol but only 7-9% at 25 micromol, suggesting a saturation of this process. 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.