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

Abstract

1. The pharmacokinetics and metabolism of KBH-A40, a novel δ-lactam-based histone deacetylase inhibitor, were characterized in male Sprague–Dawley rats. KBH-A40 exhibited a high clearance (12.0 ± 2.8 l h⁻¹kg⁻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 ± 0.3 h).

2. KBH-A40 was rapidly converted to its metabolite, KBH-A40 carboxylate, after intravenous (2 and 20 mg kg⁻¹) and oral (10 mg kg⁻¹) administration; the carboxylate metabolite remained at elevated concentrations in the plasma for more than 8 h. Glucuronide conjugate of KBH-A40 was identified qualitatively by using liquid chromatography tandem mass spectrometry in rat plasma.

3. KBH-A40 was rapidly absorbed (t_max = 0.4 h) after oral dose, consistent with its permeability in Caco-2 cells. Its oral bioavailability was low (14.2–14.8%). An apparent “double peak” phenomenon was observed for both KBH-A40 and KBH-A40 carboxylate after oral administration.

4. KBH-A40 was degraded rapidly by glucuronidation, but not by cytochrome P450-mediated oxidation, in rat liver microsomes.

5. 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.

Keywords::

• KBH-A40
• KBH-A40 carboxylate
• HDAC inhibitor
• pharmacokinetics
• glucuronidation
• hydrolysis

Acknowledgements

This research was supported by a grant from the KRIBB Research Initiative Program and the Brain Korea 21 Project.

Declaration of interest

The authors report no declarations of interest.