In vitro metabolism of KBH-A40, a novel delta-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum.
1. The metabolism of KBH-A40, a novel delta-lactam-based histone deacetylase (HDAC) inhibitor, was investigated in vitro using human liver microsomes and serum. After 60-min incubation in human liver microsomes with beta-nicotinamide adenine dinucleotide phosphate (NADPH) or uridine diphosphate glucuronic acid (UDPGA), the residual KBH-A40 was 90.6% +/- 5.1% and 28.9% +/- 2.0% (t(1/2) = 26 min), respectively, suggesting that KBH-A40 is likely predominantly metabolized by glucuronidation, rather than by cytochrome P450 (CYP)-mediated oxidation. Consistently, KBH-A40 glucuronide was the only metabolite identified following incubations of KBH-A40 with human liver microsomes in the presence of both NADPH and UDPGA. 2. KBH-A40 was not notably degraded when incubated with human serum for 60 min. In contrast, KBH-A40 was rapidly hydrolysed to its carboxylic acid form in rat serum (t(1/2) = 13 min). 3. Taken collectively, the results suggest that KBH-A40 is likely metabolized in man predominantly by glucuronidation of its hydroxamic acid moiety, with negligible biotransformation elsewhere in the molecule.
Kim
H M
HM
Bio-Evaluation Center, KRIBB, Cungbuk, Korea.
Oh
S J
SJ
Park
S-K
SK
Han
G
G
Kim
K
K
Lee
K S
KS
Kang
J S
JS
Nam
M
M
Lee
K
K
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002853:Chromatography, Liquid; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D007769:Lactams / Q000097:blood* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D011728:Pyridones / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007769:Lactams; C531962:N-hydroxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydropyridin-3-yl)propanamide; D011728:Pyridones