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 λmax 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 atm/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.
Footnotes
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Send reprint requests to: Peter C. Adamson, M.D., Children’s Hospital of Philadelphia, Abramson Pediatric Research Center, Suite 902, 3516 Civic Center Blvd., Philadelphia, PA 19104. E-mail: adamson{at}emailchop.edu
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↵1 Current address: Rainbow Babies and Children’s Hospital, Cleveland, OH 44106.
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↵2 Current address: U.S. Food and Drug Administration, Rockville, MD 20850.
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↵3 Current address: Texas Children’s Cancer Center, Houston, TX 77030.
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↵4 Current address: Children’s Hospital of Philadelphia, Philadelphia, PA 19104.
- Abbreviations:
- MP
- 6-mercaptopurine
- TG
- thioguanine
- 8-OH-TG
- 8-hydroxy-thioguanine
- CIVI
- continuous intravenous infusion
- AO
- aldehyde oxidase
- Received April 27, 1999.
- Accepted August 9, 1999.
- U.S. Government
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Thioguanine Administered as a Continuous Intravenous Infusion to Pediatric Patients Is Metabolized to the Novel Metabolite 8-Hydroxy-Thioguanine
