956 Pharmacokinetics and interconversion of the carboxylate and lactone forms of irinotecan (CPT-11) and of its metabolite SN-38 in patients

Abstract

We have developed an original HPLC method for the simultaneous analysis of the new camptothecin derivative irinotecan (CPT-11) and its active metabolite SN-38 in both their lactone and carboxylate forms. The use of the internal standard camptothecin lactone enables the detection of hydrolysis of the lactones in improperly stored samples and ensures that estimates of the ratio of the inactive (carboxylate) to active (lactone) forms determined from patient samples are accurate. We have studied the pharmacokinetics of CPT-11 and SN-38 in five patients treated with 300–500mg/m² of CPT-11 at various cycles of treatment and the following parameters for CPT-11 lactone were ob-tained: CL=39.0±9.6L/hr/m²; Vd_ss=263±102L/m²; t_1/2 α<i>=</i>3.1±1.5min; t_1/2 β=1.4±0.4hr; t_1/2 γ=9.6±3.9hr. The apparent conversion of CPT-11 lactone to its carboxylate form <i>in vivo</i> was rapid with a mean half-life of 9.5 min and the carboxylate became the predominant form of plasma CPT-11 soon after the end of the infusion. The ratio of the AUCs of the lactone to total CPT-11 was 36.8±3.5%. In contrast, SN-38 was present predominantly as the lactone at ail times and with little interpatient variability (lactone/total AUC ratio=64.0±3.4%). This may partly explain the promising activity of CPT-11 as it is known that camptothecin derivatives are active against their target, topoisomerase I, only in their lactone form.