Vol. 291, Issue 2, 870-874, November 1999

Thioguanine Administered as a Continuous Intravenous Infusion to Pediatric Patients Is Metabolized to the Novel Metabolite 8-Hydroxy-Thioguanine

Brenda J. Kitchen¹, Asher Moser, Elizabeth Lowe, Frank M. Balis, Brigitte Widemann, Lawrence Anderson², John Strong², Susan M. Blaney³, Stacey L. Berg³, Michelle O'Brien and Peter C. Adamson⁴

Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland

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 _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.