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Research ArticleArticle

NEW SECONDARY METABOLITES OF PHENYLBUTYRATE IN HUMANS AND RATS

Takhar Kasumov, Laura L. Brunengraber, Blandine Comte, Michelle A. Puchowicz, Kathryn Jobbins, Katherine Thomas, France David, Renee Kinman, Suzanne Wehrli, William Dahms, Douglas Kerr, Itzhak Nissim and Henri Brunengraber
Drug Metabolism and Disposition January 2004, 32 (1) 10-19; DOI: https://doi.org/10.1124/dmd.32.1.10
Takhar Kasumov
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Laura L. Brunengraber
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Blandine Comte
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Michelle A. Puchowicz
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Kathryn Jobbins
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Katherine Thomas
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France David
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Renee Kinman
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Suzanne Wehrli
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William Dahms
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Douglas Kerr
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Itzhak Nissim
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Henri Brunengraber
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Abstract

Phenylbutyrate is used to treat inborn errors of ureagenesis, malignancies, cystic fibrosis, and thalassemia. High-dose phenylbutyrate therapy results in toxicity, the mechanism of which is unexplained. The known metabolites of phenylbutyrate are phenylacetate, phenylacetylglutamine, and phenylbutyrylglutamine. These are excreted in urine, accounting for a variable fraction of the dose. We identified new metabolites of phenylbutyrate in urine of normal humans and in perfused rat livers. These metabolites result from interference between the metabolism of phenylbutyrate and that of carbohydrates and lipids. The new metabolites fall into two categories, glucuronides and phenylbutyrate β-oxidation side products. Two questions are raised by these data. First, is the nitrogen-excreting potential of phenylbutyrate diminished by ingestion of carbohydrates or lipids? Second, does competition between the metabolism of phenylbutyrate, carbohydrates, and lipids alter the profile of phenylbutyrate metabolites? Finally, we synthesized glycerol esters of phenylbutyrate. These are partially bioavailable in rats and could be used to administer large doses of phenylbutyrate in a sodium-free, noncaustic form.

Footnotes

  • ↵1 Abbreviations used are: PB, 4-phenylbutyrate; PAGN, phenylacetylglutamine; PA, phenylacetate; PBGN, 4-phenylbutyrylglutamine; PHB, 3-hydroxy-4-phenylbutyrate; PtC, 4-phenyl-trans-crotonate; PKB, 4-phenyl-3-ketobutyrate; TMS, trimethylsilyl; GC-MS, gas chromatography-mass spectrometry; SW, sweep width; TD, data points; COSY, correlation spectroscopy; HSQC, heteronuclear single-quantum coherence; AUC, area under the curve.

  • This work was supported by the National Institutes of Health (Research Grants DK58126, CA79495, and DK53761, and Training Grant DK07319) and the Cleveland Mt. Sinai Health Care Foundation.

    • Received May 14, 2003.
    • Accepted September 2, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (1)
Drug Metabolism and Disposition
Vol. 32, Issue 1
1 Jan 2004
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Research ArticleArticle

NEW SECONDARY METABOLITES OF PHENYLBUTYRATE IN HUMANS AND RATS

Takhar Kasumov, Laura L. Brunengraber, Blandine Comte, Michelle A. Puchowicz, Kathryn Jobbins, Katherine Thomas, France David, Renee Kinman, Suzanne Wehrli, William Dahms, Douglas Kerr, Itzhak Nissim and Henri Brunengraber
Drug Metabolism and Disposition January 1, 2004, 32 (1) 10-19; DOI: https://doi.org/10.1124/dmd.32.1.10

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Research ArticleArticle

NEW SECONDARY METABOLITES OF PHENYLBUTYRATE IN HUMANS AND RATS

Takhar Kasumov, Laura L. Brunengraber, Blandine Comte, Michelle A. Puchowicz, Kathryn Jobbins, Katherine Thomas, France David, Renee Kinman, Suzanne Wehrli, William Dahms, Douglas Kerr, Itzhak Nissim and Henri Brunengraber
Drug Metabolism and Disposition January 1, 2004, 32 (1) 10-19; DOI: https://doi.org/10.1124/dmd.32.1.10
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