Evaluation of the 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 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, t₁/₂ (2.0 ± 0.3 h). 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. 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. 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.

Discovery of Orally Available Runt-Related Transcription Factor 3 (RUNX3) Modulators for Anticancer Chemotherapy by Epigenetic Activation and Protein Stabilization

“…However, uridine 5′-diphospho­glucuronic acid (UDPGA) dependent phase II metabolism was observed for compound 4b ′ (45.7% remaining). On the basis of several studies of the metabolism of hydroxamic acid derivatives, − the hydroxamic acid moiety of 4b ′ seems to be metabolized by O-glucuronidation. Compound 4l , however, was stable against UDPGA-dependent metabolism in rat liver microsomes, with 72.4% remaining.…”