title: Stability of thioTEPA and its metabolites, TEPA, monochloroTEPA and thioTEPA-mercapturate, in plasma and urine.
abstract: The degradation of N,N',N"-triethylenethiophosphoramide (thioTEPA) and its metabolites N,N',N"-triethylenephosphoramide (TEPA), N, N'-diethylene,N"-2-chloroethylphosphoramide (monochloroTEPA) and thioTEPA-mercapturate in plasma and urine has been investigated. ThioTEPA, TEPA and monochloroTEPA were analyzed using a gas chromatographic (GC) system with selective nitrogen/phosphorous detection; thioTEPA-mercapturate was analyzed on a liquid chromatography-mass spectrometric (LC-MS) system. The influences of pH and temperature on the stability of thioTEPA and its metabolites were studied. An increase in degradation rate was observed with decreasing pH as measured for all studied metabolites. In urine the rate of degradation at 37 degrees C was approximately 2.5+/-1 times higher than at 22 degrees C. At 37 degrees C thioTEPA and TEPA were more stable in plasma than in urine, with half lives ranging from 9-20 h for urine and 13-34 h for plasma at pH 6. Mono- and dichloro derivatives of thioTEPA were formed in urine and the monochloro derivative was found in plasma. Degradation of TEPA in plasma and urine resulted in the formation of monochloroTEPA. During the degradation of TEPA in plasma also the methoxy derivative of TEPA was formed as a consequence of the applied procedure. The monochloro derivative of thioTEPA-mercapturate was formed in urine, whereas for monochloroTEPA no degradation products could be detected.
authors.affiliation: Department of Pharmaceutical Analysis, Faculty of Pharmacy, Utrecht University, Sorbonnelaan 16, 3584 CA, Utrecht, The Netherlands. m.j.vanmaanen@pharm.uu.nl
authors.forename: M J
authors.initials: MJ
authors.lastname: van Maanen
authors.forename: K
authors.initials: K
authors.lastname: Doesburg Smits
authors.forename: J M
authors.initials: JM
authors.lastname: Damen
authors.forename: A J
authors.initials: AJ
authors.lastname: Heck
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D001388:Aziridines / Q000097:blood / Q000378:metabolism* / Q000652:urine; D004355:Drug Stability; D013058:Mass Spectrometry; D013852:Thiotepa / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D013721:Triethylenephosphoramide / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000652:urine
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001388:Aziridines; C411825:N,N'-diethylene-N''-2-chloroethylphosphoramide; C411826:thioTEPA-mercapturate; D013852:Thiotepa; D013721:Triethylenephosphoramide; D000111:Acetylcysteine