title: Pharmacokinetics, metabolism, and routes of excretion of intravenous irofulven in patients with advanced solid tumors.
abstract: Irofulven is currently in Phase 2 clinical trials against a wide variety of solid tumors and has demonstrated activity in ovarian, prostate, gastrointestinal, and non-small cell lung cancer. The objectives of this study were to determine its pharmacokinetics and route of excretion and to characterize its metabolites in human plasma and urine samples after a 30-min i.v. infusion at a dose of 0.55 mg/kg in patients with advanced solid tumors. Three patients were administered i.v. 100 microCi of [14C]irofulven over a 30-min infusion on day 1 of cycle 1. Serial blood and plasma samples were drawn at 0 (before irofulven infusion) and up to 144 h after the start of infusion. Urine and fecal samples were collected for up to 144 h after the start of infusion. The mean urinary and fecal excretion of radioactivity up to 144 h were 71.2 and 2.9%, respectively, indicating renal excretion was the major route of elimination of [14C]irofulven. The C(max), AUC(0-infinity), and terminal half-life values for total radioactivity were 1130 ng-Eq/ml, 24,400 ng-Eq . h/ml, and 116.5 h, respectively, and the corresponding values for irofulven were 82.7 ng/ml, 65.5 ng . h/ml, and 0.3 h, respectively, suggesting that the total radioactivity in human plasma was a result of the metabolites. Twelve metabolites of irofulven were detected in human urine and plasma by electrospray ionization/tandem mass spectrometry. Among these metabolites, the cyclopropane ring-opened metabolite (M2) of irofulven was found, and seven others were proposed as glucuronide and glutathione conjugates.
authors.affiliation: Unité Propre de Recherche et de l'Enseignement Supérieur, Equipe d'Accueil, Pharmacology and New Treatments of Cancer, l'Institut Fédératif de Recherches, Institute Gustave Roussy, Villejuif, France.
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.forename: Keyvan
authors.initials: K
authors.lastname: Rezai
authors.forename: Alain
authors.initials: A
authors.lastname: Deroussent
authors.forename: Dominique
authors.initials: D
authors.lastname: De Valeriola
authors.forename: Micheline
authors.initials: M
authors.lastname: Re
authors.forename: Sophie
authors.initials: S
authors.lastname: Weill
authors.forename: Esteban
authors.initials: E
authors.lastname: Cvitkovic
authors.forename: Carmen
authors.initials: C
authors.lastname: Kahatt
authors.forename: Ajit
authors.initials: A
authors.lastname: Shah
authors.forename: Stephen
authors.initials: S
authors.lastname: Waters
authors.forename: Gary
authors.initials: G
authors.lastname: Weems
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: François
authors.initials: F
authors.lastname: Lokiec
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012717:Sesquiterpenes / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D021241:Spectrometry, Mass, Electrospray Ionization; D014018:Tissue Distribution
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002250:Carbon Radioisotopes; D012717:Sesquiterpenes; C102714:irofulven