Pharmacokinetic interrelationships of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials.
Irinotecan (CPT-11) is an analogue of 20(S)-camptothecin with promising activity against several tumor types. In patients, CPT-11 is metabolized to 7-ethyl-10-hydroxycamptothecin (SN-38) and to the beta-glucuronide of SN-38. Recently, we identified an additional metabolite of CPT-11, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC; L. P. Rivory et al. , Cancer Res., 56: 3689-3694, 1996). The aim of this study was to investigate the interrelationships of all four compounds to identify factors that might be responsible for the large interpatient variability in CPT-11 and SN-38 kinetics. The plasma kinetics of CPT-11, SN-38, the beta-glucuronide of SN-38, and APC were studied in 19 patients for a total of 33 cycles (115-600 mg/m2). Although the area under the concentration curves (AUCs) of all compounds studied increased with dose, there was considerable variability. Ratios of the AUCs of the appropriate compounds were used as estimates of the major routes of metabolism (conversion of CPT-11 to SN-38, metabolism of CPT-11 to APC, and glucuronidation of SN-38). Each ratio varied more than 10-fold across the patient population, and the apparent extent of conversion of CPT-11 to SN-38 was highest at the 115 mg/m2 dose level. Interestingly, AUCSN-38 was greater in patients with both high AUCCPT-11 and AUCAPC. We conclude that the variability of the pharmacokinetics of CPT-11 and SN-38 is likely to be due to extensive interpatient differences in the pathways implicated in the metabolism of CPT-11.
Rivory
L P
LP
Department of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. Lrivory@gpo.pa.up.edu.au
Haaz
M C
MC
Canal
P
P
Lokiec
F
F
Armand
J P
JP
Robert
J
J
D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001711:Biotransformation; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005602:France; D005965:Glucuronates / Q000097:blood; D006801:Humans; D000077146:Irinotecan; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*
C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; C100720:RPR 121056; D000077146:Irinotecan; D002166:Camptothecin