Pharmacokinetics of irinotecan and its metabolites in human blood,bile, and urine

Two patients were treated with CPT-11 for colorectal cancer and had a percutaneous biliary catheter for extrahepatic biliary obstruction. The first patient was treated with CPT-11 according to the 100-mg/m² weekly therapeutic schedule, and the second patient was treated every 3 weeks, with a dose of 350 mg/m² being given at the first course, after which it was decreased to 300 mg/m² for the following courses. In plasma, the active identified metabolite of CPT-11, SN-38, occurred mainly in the form of a glucuronide conjugate. CPT-11 was mainly excreted in bile and urine as CPT-11. The cumulative biliary and urinary excretion of CPT-11 and its metabolites (SN-38 and SN-38 glucuronide conjugate) over a period of up to 48 h ranged from 25% (100 mg/m² weekly) to 50% (300 mg/m² every 3 weeks). This means that CPT-11 can be excreted under other, not yet identified metabolite forms. CPT-11 is active in vivo, the intensity of its in vitro activity seems rather low. It has been suggested that its major identified metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38) plays a key role in the antitumor activity of CPT-11 [4]. Some in vitro data suggest that SN-38 is 250-to 1,000-fold as potent as CPT-11 in the inhibition of topoisomerase I activity [5]. Although a glucuronide of SN-38 has been found in the bile and urine of rats [3], data have not been reported on humans. However, only Rothenberg et al. [10] have studies the bile concentrations of CPT-11 and SN-38. This report summarizes the pharmacokinetics of CPT-11 and SN-38 and their glucuronide metabolites in the blood, bile, and urine of two patients treated with CPT-11.