title: Metabolic activation of irinotecan during intra-arterial chemotherapy of metastatic colorectal cancer.
abstract: Biotransformation of irinotecan (CPT-11) into its pharmacologic active metabolite SN-38 was investigated in patients treated for advanced colorectal cancer. A dose of 180 mg/m(2) CPT-11 was administered to 6 patients by 60 min hepatic intra-arterial infusion (HAI) via a surgically implanted Port-a-Cath® system. Blood samples were collected from 0 to 360 min after start of HAI, and CPT-11 plus metabolites were analysed by a selective reversed phase HPLC method. The objective of this study was to evaluate the extent to which SN-38 is generated after HAI of irinotecan given at a low dose of 180 mg/m(2). In a second investigation, CPT-11 was administered via conventional intravenous infusion (dose 180 mg/m(2), 60 min infusion time, 11 patients) and CPT-11 plus metabolites were quantified using identical analytical procedure. Compared to i.v. infusion, the pharmacokinetics of CPT-11 and SN-38 were altered by HAI. The mean c(max) of CPT-11 after HAI was reduced by 37%, whereas the mean c(max) of SN-38 increased by 60%. HAI resulted in a desired, increased metabolic conversion of CPT-11 into SN-38 and might improve the regional availability of the pharmacologic active metabolite SN-38 at the site of tumor. Plasma concentrations of the metabolites SN-38 glucuronide and APC remained unaffected by the route of administration.
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, Center of Pharmacy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. martin.czejka@univie.ac.at
authors.forename: M
authors.initials: M
authors.lastname: Czejka
authors.forename: A
authors.initials: A
authors.lastname: Kiss
authors.forename: C
authors.initials: C
authors.lastname: Koessner
authors.forename: R
authors.initials: R
authors.lastname: Terkola
authors.forename: D
authors.initials: D
authors.lastname: Ettlinger
authors.forename: J
authors.initials: J
authors.lastname: Schueller
mesh_terms: D000368:Aged; D001711:Biotransformation; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007261:Infusions, Intra-Arterial; D000077146:Irinotecan; D008875:Middle Aged; D009362:Neoplasm Metastasis; D013997:Time Factors
chemical_list: D000077146:Irinotecan; D002166:Camptothecin