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

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.