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Research ArticleArticle

PLASMA PHARMACOKINETICS AND METABOLISM OF THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A AFTER INTRAPERITONEAL ADMINISTRATION TO MICE

L. Sanderson, G. W. Taylor, E. O. Aboagye, J. P. Alao, J. R. Latigo, R. C. Coombes and D. M. Vigushin
Drug Metabolism and Disposition October 2004, 32 (10) 1132-1138; DOI: https://doi.org/10.1124/dmd.104.000638
L. Sanderson
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G. W. Taylor
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E. O. Aboagye
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J. P. Alao
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J. R. Latigo
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R. C. Coombes
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D. M. Vigushin
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Abstract

Trichostatin A is a potent and specific histone deacetylase inhibitor with promising antitumor activity in preclinical models. Plasma pharmacokinetics of trichostatin A were studied following single-dose intraperitoneal administration of 80 mg/kg (high dose) or 0.5 mg/kg (low dose) to female BALB/c mice. Plasma trichostatin A concentrations were quantified by high performance liquid chromatography (HPLC)-UV assay (high dose) or by HPLC-multiple reaction monitoring assay (low dose). Trichostatin A was rapidly absorbed from the peritoneum and detectable in plasma within 2 min. Cmax of 40 μg/ml and 8 ng/ml occurred within 5 min, followed by rapid exponential decay in plasma trichostatin A concentration with t1/2 of 6.3 min and 9.6 min (high and low doses, respectively). Phase I metabolites at the high dose were identified by simultaneous UV and positive ion electrospray mass spectrometry. Trichostatin A underwent extensive metabolism: primary metabolic pathways were N-demethylation, reduction of the hydroxamic acid to the corresponding trichostatin A amide, and oxidative deamination to trichostatic acid. N-Monomethyl trichostatin A amide was the major plasma metabolite. No didemethylated compounds were identified. Trichostatic acid underwent further biotransformation: reduction and β-oxidation of the carboxylic acid, with or without N-demethylation, resulted in formation of dihydro trichostatic acid and dinor dihydro trichostatic acids. HPLC fractions corresponding to trichostatin A and N-demethylated trichostatin A exhibited histone deacetylase-inhibitory activity; no other fractions were biologically active. We conclude that trichostatin A is rapidly and extensively metabolized in vivo following intraperitoneal administration to mice, and N-demethylation does not compromise histone deacetylase-inhibitory activity.

Footnotes

  • Grant support for this work from the National Translational Cancer Research Network and The Mandeville Trust is gratefully acknowledged. The Section of Proteomics is a joint facility funded by Imperial College Division of Medicine and the Medical Research Council Clinical Sciences Centre.

  • doi:10.1124/dmd.104.000638.

  • ABBREVIATIONS: HPLC, high performance liquid chromatography; MS/MS, tandem mass spectrometry; ESP, positive ion electrospray ionization; MRM, multiple reaction monitoring.

    • Received May 14, 2004.
    • Accepted July 12, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (10)
Drug Metabolism and Disposition
Vol. 32, Issue 10
1 Oct 2004
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Research ArticleArticle

PLASMA PHARMACOKINETICS AND METABOLISM OF THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A AFTER INTRAPERITONEAL ADMINISTRATION TO MICE

L. Sanderson, G. W. Taylor, E. O. Aboagye, J. P. Alao, J. R. Latigo, R. C. Coombes and D. M. Vigushin
Drug Metabolism and Disposition October 1, 2004, 32 (10) 1132-1138; DOI: https://doi.org/10.1124/dmd.104.000638

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Research ArticleArticle

PLASMA PHARMACOKINETICS AND METABOLISM OF THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A AFTER INTRAPERITONEAL ADMINISTRATION TO MICE

L. Sanderson, G. W. Taylor, E. O. Aboagye, J. P. Alao, J. R. Latigo, R. C. Coombes and D. M. Vigushin
Drug Metabolism and Disposition October 1, 2004, 32 (10) 1132-1138; DOI: https://doi.org/10.1124/dmd.104.000638
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