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

Brenda J. Kitchen; Asher Moser; Elizabeth Lowe; Frank M. Balis; Brigitte Widemann; Lawrence Anderson; John Strong; Susan M. Blaney; Stacey L. Berg; Michelle O'Brien; Peter C. Adamson

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

Brenda J. Kitchen, Asher Moser, Elizabeth Lowe, Frank M. Balis, Brigitte Widemann, Lawrence Anderson, John Strong, Susan M. Blaney, Stacey L. Berg, Michelle O'Brien, Peter C. Adamson

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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 λ(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 pre-dominant circulating metabolite found in patients receiving CIVI-TG and is likely generated by the action of aldehyde oxidase.

Original language	English
Pages (from-to)	870-874
Number of pages	5
Journal	Journal of Pharmacology and Experimental Therapeutics
Volume	291
Issue number	2
State	Published - 1 Nov 1999
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Pharmacology

Cite this

Kitchen, B. J., Moser, A., Lowe, E., Balis, F. M., Widemann, B., Anderson, L., Strong, J., Blaney, S. M., Berg, S. L., O'Brien, M., & Adamson, P. C. (1999). Thioguanine administered as a continuous intravenous infusion to pediatric patients is metabolized to the novel metabolite 8-hydroxy- thioguanine. Journal of Pharmacology and Experimental Therapeutics, 291(2), 870-874.

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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 λ(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 pre-dominant circulating metabolite found in patients receiving CIVI-TG and is likely generated by the action of aldehyde oxidase.",

author = "Kitchen, {Brenda J.} and Asher Moser and Elizabeth Lowe and Balis, {Frank M.} and Brigitte Widemann and Lawrence Anderson and John Strong and Blaney, {Susan M.} and Berg, {Stacey L.} and Michelle O'Brien and Adamson, {Peter C.}",

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Thioguanine administered as a continuous intravenous infusion to pediatric patients is metabolized to the novel metabolite 8-hydroxy- thioguanine. / Kitchen, Brenda J.; Moser, Asher; Lowe, Elizabeth et al.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 291, No. 2, 01.11.1999, p. 870-874.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Thioguanine administered as a continuous intravenous infusion to pediatric patients is metabolized to the novel metabolite 8-hydroxy- thioguanine

AU - Kitchen, Brenda J.

AU - Moser, Asher

AU - Lowe, Elizabeth

AU - Balis, Frank M.

AU - Widemann, Brigitte

AU - Anderson, Lawrence

AU - Strong, John

AU - Blaney, Susan M.

AU - Berg, Stacey L.

AU - O'Brien, Michelle

AU - Adamson, Peter C.

PY - 1999/11/1

Y1 - 1999/11/1

N2 - 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 λ(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 pre-dominant circulating metabolite found in patients receiving CIVI-TG and is likely generated by the action of aldehyde oxidase.

AB - 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 λ(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 pre-dominant circulating metabolite found in patients receiving CIVI-TG and is likely generated by the action of aldehyde oxidase.

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

Abstract

ASJC Scopus subject areas

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