Evaluation of the pharmacokinetics and metabolism of a novel histone deacetylase inhibitor, KBH-A40, in rats

S. J. Oh, K. Lee, J. Ryu, H. E. Yu, G. Han, S. K. Park, J. S. Kang, H. M. Kim, Y. C. Kim

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Abstract

The pharmacokinetics and metabolism of KBH-A40, a novel δ-lactam-based histone deacetylase inhibitor, were characterized in male SpragueDawley rats. KBH-A40 exhibited a high clearance (12.0±2.8 l h -1kg-1), a large volume of distribution at steady state, Vss (3.9±1.5 l kg-1), and a short half-life, t 1/2 (2.0±0.3h). KBH-A40 was rapidly converted to its metabolite, KBH-A40 carboxylate, after intravenous (2 and 20mg kg-1) and oral (10mg kg-1) administration; the carboxylate metabolite remained at elevated concentrations in the plasma for more than 8h. Glucuronide conjugate of KBH-A40 was identified qualitatively by using liquid chromatography tandem mass spectrometry in rat plasma. KBH-A40 was rapidly absorbed (t max=0.4h) after oral dose, consistent with its permeability in Caco-2 cells. Its oral bioavailability was low (14.214.8%). An apparent "double peak" phenomenon was observed for both KBH-A40 and KBH-A40 carboxylate after oral administration. KBH-A40 was degraded rapidly by glucuronidation, but not by cytochrome P450-mediated oxidation, in rat liver microsomes. These results suggest that the rapid metabolism of KBH-A40 could be a major reason for its poor pharmacokinetics. Therefore, this work provides valuable structural information to improve pharmacokinetic properties of KBH-A40, a lead compound.

Original languageEnglish
Pages (from-to)155-163
Number of pages9
JournalXenobiotica
Volume41
Issue number2
DOIs
Publication statusPublished - 2011 Feb

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis

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    Oh, S. J., Lee, K., Ryu, J., Yu, H. E., Han, G., Park, S. K., Kang, J. S., Kim, H. M., & Kim, Y. C. (2011). Evaluation of the pharmacokinetics and metabolism of a novel histone deacetylase inhibitor, KBH-A40, in rats. Xenobiotica, 41(2), 155-163. https://doi.org/10.3109/00498254.2010.531790