title: Detection of new exemestane metabolites by liquid chromatography interfaced to electrospray-tandem mass spectrometry.
abstract: Exemestane is an irreversible aromatase inhibitor used for anticancer therapy. Unfortunately, this drug is also misused in sports to avoid some adverse effects caused by steroids administration. For this reason exemestane has been included in World Anti-Doping Agency prohibited list. Usually, doping control laboratories monitor prohibited substances through their metabolites, because parent compounds are readily metabolized. Thus metabolism studies of these substances are very important. Metabolism of exemestane in humans is not clearly reported and this drug is detected indirectly through analysis of its only known metabolite: 17β-hydroxyexemestane using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and gas chromatography coupled to mass spectrometry (GC-MS). This drug is extensively metabolized to several unknown oxidized metabolites. For this purpose LC-MS/MS has been used to propose new urinary exemestane metabolites, mainly oxidized in C6-exomethylene and simultaneously reduced in 17-keto group. Urine samples from four volunteers obtained after administration of a 25mg dose of exemestane were analyzed separately by LC-MS/MS. Urine samples of each volunteer were hydrolyzed followed by liquid-liquid extraction and injected into a LC-MS/MS system. Three unreported metabolites were detected in all urine samples by LC-MS/MS. The postulated structures of the detected metabolites were based on molecular formulae composition obtained through high accuracy mass determination by liquid chromatography coupled to hybrid quadrupole-time of flight mass spectrometry (LC-QTOF MS) (all mass errors below 2ppm), electrospray (ESI) product ion spectra and chromatographic behavior.
authors.affiliation: Universidade Federal do Rio de Janeiro, Instituto de Química, Programa de Pós-Graduação em Química, LAB DOP - LADETEC, Rio de Janeiro, Brazil. gcavalcanti83@yahoo.com.br
authors.forename: Gustavo
authors.initials: G
authors.lastname: de Albuquerque Cavalcanti
authors.forename: Bruno
authors.initials: B
authors.lastname: Carius Garrido
authors.forename: Felipe
authors.initials: F
authors.lastname: Dias Leal
authors.forename: Monica
authors.initials: M
authors.lastname: Costa Padilha
authors.forename: Monica
authors.initials: M
authors.lastname: Mazzarino
authors.forename: Xavier
authors.initials: X
authors.lastname: de la Torre
authors.forename: Francesco
authors.initials: F
authors.lastname: Botre
authors.forename: Francisco
authors.initials: F
authors.lastname: Radler de Aquino Neto
mesh_terms: D000328:Adult; D000730:Androstadienes / Q000378:metabolism* / Q000652:urine; D047072:Aromatase Inhibitors / Q000378:metabolism* / Q000652:urine; D002853:Chromatography, Liquid / Q000379:methods*; D004300:Doping in Sports; D006801:Humans; D008297:Male; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D015813:Substance Abuse Detection / Q000379:methods*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; C056516:exemestane