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, Gyoonhee Han, S. K. Park, J. S. Kang, H. M. Kim, Y. C. Kim

Research output: Contribution to journalArticle

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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 -1 kg -1 ), a large volume of distribution at steady state, V ss (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 1

Fingerprint

Histone Deacetylase Inhibitors
Pharmacokinetics
Metabolism
Rats
Metabolites
N-hydroxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydropyridin-3-yl)propanamide
Lead compounds
Plasmas
Lactams
Caco-2 Cells
Glucuronides
Liquid chromatography
Liver Microsomes
Tandem Mass Spectrometry
Liquid Chromatography
Liver
Cytochrome P-450 Enzyme System
Biological Availability
Mass spectrometry
Oral Administration

All Science Journal Classification (ASJC) codes

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

Cite this

Oh, S. J. ; Lee, K. ; Ryu, J. ; Yu, H. E. ; Han, Gyoonhee ; Park, S. K. ; Kang, J. S. ; Kim, H. M. ; Kim, Y. C. / Evaluation of the pharmacokinetics and metabolism of a novel histone deacetylase inhibitor, KBH-A40, in rats. In: Xenobiotica. 2011 ; Vol. 41, No. 2. pp. 155-163.
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Evaluation of the pharmacokinetics and metabolism of a novel histone deacetylase inhibitor, KBH-A40, in rats. / Oh, S. J.; Lee, K.; Ryu, J.; Yu, H. E.; Han, Gyoonhee; Park, S. K.; Kang, J. S.; Kim, H. M.; Kim, Y. C.

In: Xenobiotica, Vol. 41, No. 2, 01.02.2011, p. 155-163.

Research output: Contribution to journalArticle

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