Evaluation of the pharmacokinetics and metabolism of a novel histone deacetylase inhibitor, KBH-A40, in rats.
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.
College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
S J
SJ
Oh
K
K
Lee
J
J
Ryu
H E
HE
Yu
G
G
Han
S K
SK
Park
J S
JS
Kang
H M
HM
Kim
Y C
YC
Kim
D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D020719:Glucuronides / Q000097:blood / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D020719:Glucuronides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C531962:N-hydroxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydropyridin-3-yl)propanamide; D011728:Pyridones