Thioguanine administered as a continuous intravenous infusion to pediatricpatients is metabolized to the novel metabolite 8-hydroxy-thioguanine

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 t hioguanine (CIVI-TG) suggested that TG was eliminated by saturable mechanis m, with conversion of the drug to an unknown metabolite. In this study we h ave identified this metabolite as 8-hydroxy-thioguanine (8-OH-TG). The meta bolite coeluted with the 8-OH-TG standard on HPLC and had an identical UV s pectrum, with a lambda(max) of 350 nm. On mass spectroscopy, the positive i on, single quad scan of 8-OH-TG yielded a protonated molecular ion at 184 D a and contained diagnostic ions at m/z 167, 156, 142, and 125 Da. Incubatio n 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 pa tients receiving CIVI-TG and is likely generated by the action of aldehyde oxidase.