Kinetics of the in vivo interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients.

The kinetics of the in vivo interconversion of the carboxylate and lactone forms of the prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin (CPT-11), and its active metabolite SN-38 were studied in five patients using a HPLC method that allows the simultaneous determination of all four compounds and detects any hydrolysis of lactones due to inadequate sample handling and storage. The apparent conversion of CPT-11 lactone to the carboxylate in vivo was rapid with a mean half-life of 9.5 min; the carboxylate became the predominant form of plasma CPT-11 soon after the end of the infusion. The ratio of the area under the plasma concentration-time curves of the lactone to total CPT-11 was 36.8 +/- 3.5% (SD). In contrast, SN-38 was present predominantly as the lactone at all times and with little interpatient variability (lactone/total area under the plasma concentration-time curve ratio, 64.0 +/- 3.4%). This may explain in part the promising activity of CPT-11 because CPT derivatives are active against their target, topoisomerase I, only in their lactone form.