PT  - JOURNAL ARTICLE
AU  - Angelo Paci
AU  - Keyvan Rezai
AU  - Alain Deroussent
AU  - Dominique De Valeriola
AU  - Micheline Re
AU  - Sophie Weill
AU  - Esteban Cvitkovic
AU  - Carmen Kahatt
AU  - Ajit Shah
AU  - Stephen Waters
AU  - Gary Weems
AU  - Gilles Vassal
AU  - François Lokiec
TI  - Pharmacokinetics, Metabolism, and Routes of Excretion of Intravenous Irofulven in Patients with Advanced Solid Tumors
AID  - 10.1124/dmd.106.010512
DP  - 2006 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1918--1926
VI  - 34
IP  - 11
4099  - http://dmd.aspetjournals.org/content/34/11/1918.short
4100  - http://dmd.aspetjournals.org/content/34/11/1918.full
SO  - Drug Metab Dispos2006 Nov 01; 34
AB  - 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 μCi 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 Cmax, AUC0-∞, 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. The American Society for Pharmacology and Experimental Therapeutics