title: Identification and kinetics of a beta-glucuronide metabolite of SN-38 in human plasma after administration of the camptothecin derivative irinotecan.
abstract: Irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycampothecin) , also known as CPT-11, is a promising semi-synthetic derivative of camptothecin with significant activity against a range of tumor types. The pharmacokinetic behaviour of its principal and presumedly active metabolite, SN-38 (7-ethyl-10-hydroxy-camptothecin), displays wide inter-patient variation. During the high-performance liquid chromatographic (HPLC) analysis of plasma samples collected from a patient given CPT-11, we observed several unidentified peaks that were not present in pre-infusion samples. In this paper we describe the manner in which one of these was determined to be a beta-glucuronide of SN-38. The total plasma concentrations of this metabolite were quantified following digestion with beta-glucuronidase and were found to be greater than those of SN-38 in the patient studied. The elimination phases of the plasma concentration profile of SN-38 and its glucuronide were parallel, suggesting that the transformation of SN-38 to the glucuronide is the rate-limiting step in the elimination of SN-38 and could play a key role in its pharmacokinetics.
authors.affiliation: University of Bordeaux II, France.
authors.forename: L P
authors.initials: LP
authors.lastname: Rivory
authors.forename: J
authors.initials: J
authors.lastname: Robert
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood* / Q000493:pharmacokinetics; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy; D005260:Female; D005965:Glucuronates / Q000097:blood*; D005966:Glucuronidase; D006801:Humans; D000077146:Irinotecan; D008875:Middle Aged; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; D000077146:Irinotecan; D005966:Glucuronidase; D002166:Camptothecin