title: Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man.
abstract: Ecteinascidin 743 (ET-743) is a potent anti-tumoral agent of a marine origin. It is currently being tested in phase II clinical trials using a 3-weekly 24-h i.v. infusion of 1500 microg/m(2) and 3-h infusions of 1650 microg/m(2). Knowledge of the metabolism of ET-743 is, however, still scarce. In the present study, a qualitative chromatographic discovery of metabolites of ET-743 in man is reported. ET-743 and its demethylated analog ET-729 were incubated at 37 degrees C in the presence of enzyme systems, pooled human microsomes, pooled human plasma and uridine 5'-diphosphoglucuronyltransferase, respectively, in appropriate media. Reaction products were investigated chromatographically using photodiode array and ion spray-mass spectrometric detection (LC-MS). The main reaction products in microsomal incubations of ET-743 resulted from a remarkable breakdown of the molecule. In plasma the drugs were deacetylated, and the transferase did actually yield a glucuronide of both ET-743 and ET-729. In contrast, screening of urine, plasma and bile, collected from patients treated with ET-743 at the highest dose levels, using a sensitive LC-MS assay, did not result in detection of ET-729 and metabolites which were generated in vitro. The urinary excretion of ET-743 in man was lower than 0.7% of the administered dose for a 24-h infusion.
authors.affiliation: Faculty of Pharmacy, Department of Biomedical Analysis, Division of Drug Toxicology, Utrecht University, 3584 CA Utrecht, The Netherlands. R.W.Sparidans@pharm.uu.nl
authors.forename: R W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.forename: M J
authors.initials: MJ
authors.lastname: Hillebrand
authors.forename: L
authors.initials: L
authors.lastname: López-Lázaro
authors.forename: J M
authors.initials: JM
authors.lastname: Jimeno
authors.forename: I
authors.initials: I
authors.lastname: Manzanares
authors.forename: C
authors.initials: C
authors.lastname: van Kesteren
authors.forename: E
authors.initials: E
authors.lastname: Cvitkovic
authors.forename: A T
authors.initials: AT
authors.lastname: van Oosterom
authors.forename: J H
authors.initials: JH
authors.lastname: Schellens
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004149:Dioxoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008862:Microsomes, Liver / Q000378:metabolism*; D010949:Plasma / Q000378:metabolism*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D020719:Glucuronides; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C100350:ecteinascidin 729; D014453:Glucuronosyltransferase; D000077606:Trabectedin