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

  1. Brenda J. Kitchen1,
  2. Asher Moser,
  3. Elizabeth Lowe,
  4. Frank M. Balis,
  5. Brigitte Widemann,
  6. Lawrence Anderson2,
  7. John Strong2,
  8. Susan M. Blaney3,
  9. Stacey L. Berg3,
  10. Michelle O’Brien and
  11. Peter C. Adamson4
  1. Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland

    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

    • 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

    • ↵1 Current address: Rainbow Babies and Children’s Hospital, Cleveland, OH 44106.

    • ↵2 Current address: U.S. Food and Drug Administration, Rockville, MD 20850.

    • ↵3 Current address: Texas Children’s Cancer Center, Houston, TX 77030.

    • ↵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.
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    1. JPET November 1, 1999 vol. 291 no. 2 870-874
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