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.

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Supported in part by the Association pour la Recherche sur le Cancer (France) and the Groupement des Entreprises Françaises dans la Lutte Contre le Cancer. L. P. R. is the reçipient of a NHMRC/INSERM Exchange Fellowship.

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