Pharmacological Correlation between Total Drug Concentration and Lactones of CPT‐11 and SN‐38 in Patients Treated with CPT‐11

The pharmacokinetics of 7‐ethyl‐10‐[4‐(1‐piperidino)‐1‐piperidino]carbonyloxycamptothecin (CPT‐11) and its active metabolite, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), were examined to establish the pharmacokinetic variability of the active lactones of CPT‐11 and SN‐38 in comparison with that of the total (lactone and carboxylates) plasma CPT‐11 and SN‐38. Twelve patients with malignancies were entered in the study. All received 100 mg/m(2) of CPT‐11 by intravenous drip infusion over 90 min. Blood was sampled at 10 time points in heparin‐containing syringes. Analysis by high‐performance liquid chromatography showed that the ratio of CPT‐11 lactone to total CPT‐11 concentration was highest (66%) just after the end of infusion and gradually decreased to 30% at 24 h. Almost 70% of SN‐38 lactone was detected after the end of infusion and this decreased to 50% within 24 h. The standard errors of percent lactone of CPT‐11 or SN‐38 to total drug concentration at each sampling point were less than 12%. The area under the concentration‐time curve (AUC) of total CPT‐11 and that of total SN‐38 were significantly correlated with the AUCs of the lactone CPT‐11 and those of lactone SN‐38, respectively. We conclude that, for practical purposes, monitoring of total CPT‐11 and SN‐38 has essentially the same clinical significance as monitoring of lactone CPT‐11 and SN‐38.