Xie, Rujia1, Mathijssen, Ron H. J.2, Sparreboom, Alex2 and Karlsson, Mats O.1
1Division of Pharmacokinetics and Drug Therapy, Uppsala University, Sweden. 2Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, the Netherlands.
The pharmacokinetics of irinotecan (CPT-11) and four of its metabolites were studied in seventy cancer patients receiving short-term (about 1.5 h) intravenous infusions in the dose range of 175-300 mg/m2. Plasma concentrations of lactone and total CPT-11 and 7-ethyl-10-hydroxycamptothecin (SN-38), total SN-38 glucuronide, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecine (APC) and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecine (NPC) were observed. Population pharmacokinetic models, including interconversion between lactone and acid forms of CPT-11 and SN-38, were developed.
CPT-11 lactone and total concentration-time profiles could be described by a model combing three- and two-compartment models for lactone and carboxylate, respectively, with interconversion between lactone and carboxylate forms in the central as well as the peripheral compartments. CPT-11 lactone has higher CL (74.3 L/h) than that of carboxylate (12.3 L/h) and a more extensive distribution (Vss 444.6 L) than that of the carboxylate (Vss 78.7 L). The analysis pointed to a peripheral interconversion between lactone and carbxylate forms, as well as a largely unidirectional return of carboxylate from the peripheral to the central compartment. SN-38 lactone showed two-compartment, and SN-38 carboxylate and SN-38 G, one-compartment kinetics. The analysis indicated SN-38 lactone to be a major metabolite of CPT-11 lactone. Unlike CPT-11, SN-38 lactone and carboxylate forms had similar clearances (CL/Fm) of 2220 L/h and 2030 L/h, respectively. A two-compartment model adequately described APC or NPC data. From the modeling analysis, it was indicated that APC and NPC were minor metabolites mainly formed from CPT-11 carboxylate and lactone, respectively.
The analysis of complex metabolic schemes requires insight in metabolic pathways, but discrimination between some alternatives, and qualitative or semi-quantitative information about the importance of a metabolic pathway may be obtained even if the information stems from plasma concentrations following administration of the parent compound only.
Reference: PAGE 10 (2001) Abstr 200 [www.page-meeting.org/?abstract=200]
Poster: poster