title: Human metabolism of [(14)C]indisulam following i.v. infusion in cancer patients.
abstract: Indisulam is a new anticancer drug with a unique mechanism of action, arresting the cell cycle at the G1/S transition. The major excretory pathway of indisulam is via the urine, accounting for 63% of the radioactive dose ([(14)C]indisulam) administered in a human mass balance study. Radiochromatographic profiling of urine samples resulted in the detection of several radioactive peaks. The purpose of the present investigation was to elucidate the chemical structures of these observed indisulam metabolites. We collected fractions after chromatographic separation of the urine samples. These fractions were analysed using tandem mass spectrometry. We propose the chemical structure of 15 indisulam metabolites in urine. The metabolism of indisulam is very complex, consisting of oxidative dechlorination, hydroxylation, hydrolysis, acetylation, sulphation and glucuronidation. The clinical relevance of the observed indisulam metabolites needs further investigation.
authors: Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands. beumerjh@upmc.edu
authors: Jan-Hendrik
authors: JH
authors: Beumer
authors: Michel J X
authors: MJ
authors: Hillebrand
authors: Dick
authors: D
authors: Pluim
authors: Hilde
authors: H
authors: Rosing
authors: Karen
authors: K
authors: Foley
authors: S Murray
authors: SM
authors: Yule
authors: Jan H M
authors: JH
authors: Schellens
authors: Jos H
authors: JH
authors: Beijnen
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D002250:Carbon Radioisotopes; D005591:Chemical Fractionation; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D009369:Neoplasms / Q000378:metabolism* / Q000652:urine; D021241:Spectrometry, Mass, Electrospray Ionization; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000652:urine; D014556:Urine / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors; D020719:Glucuronides; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides