title: Thioguanine administered as a continuous intravenous infusion to pediatric patients is metabolized to the novel metabolite 8-hydroxy-thioguanine.
abstract: Thiopurine antimetabolites have been in clinical use for more than 40 years, yet the metabolism of thiopurines remains only partially understood. Data from our previous pediatric phase 1 trial of continuous i.v. infusion of thioguanine (CIVI-TG) suggested that TG was eliminated by saturable mechanism, with conversion of the drug to an unknown metabolite. In this study we have identified this metabolite as 8-hydroxy-thioguanine (8-OH-TG). The metabolite coeluted with the 8-OH-TG standard on HPLC and had an identical UV spectrum, with a lambda(max) of 350 nm. On mass spectroscopy, the positive ion, single quad scan of 8-OH-TG yielded a protonated molecular ion at 184 Da and contained diagnostic ions at m/z 167, 156, 142, and 125 Da. Incubation of TG in vitro with partially purified aldehyde oxidase resulted in 8-OH-TG formation. 8-OH-TG is the predominant circulating metabolite found in patients receiving CIVI-TG and is likely generated by the action of aldehyde oxidase.
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Kitchen
authors.forename: A
authors.initials: A
authors.lastname: Moser
authors.forename: E
authors.initials: E
authors.lastname: Lowe
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
authors.forename: B
authors.initials: B
authors.lastname: Widemann
authors.forename: L
authors.initials: L
authors.lastname: Anderson
authors.forename: J
authors.initials: J
authors.lastname: Strong
authors.forename: S M
authors.initials: SM
authors.lastname: Blaney
authors.forename: S L
authors.initials: SL
authors.lastname: Berg
authors.forename: M
authors.initials: M
authors.lastname: O'Brien
authors.forename: P C
authors.initials: PC
authors.lastname: Adamson
mesh_terms: D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000502:physiology*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D002648:Child; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D013058:Mass Spectrometry; D013866:Thioguanine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*
chemical_list: C400279:8-hydroxythioguanine; D000964:Antimetabolites, Antineoplastic; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase; D013866:Thioguanine