In vitro metabolism of KBH-A40, a novel δ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum

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Title
In vitro metabolism of KBH-A40, a novel δ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum
Author(s)
Hwan Mook Kim; Soo Jin Oh; Song Kyu Park; G Han; K J Kim; K S Lee; Jong Soon Kang; M Nam; Kiho Lee
Bibliographic Citation
Xenobiotica, vol. 38, no. 3, pp. 281-293
Publication Year
2008
Abstract
1. The metabolism of KBH-A40, a novel δ-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 β-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% (t1/2 = 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 (t1/2 = 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.
Keyword
GlucuronidationHistone deacetylaseHydrolysisHydroxamic acid glucuronidationKBH-A40
ISSN
0049-8254
Publisher
T&F (Taylor & Francis)
DOI
http://dx.doi.org/10.1080/00498250701813222
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of National Bio-Infrastructure > Laboratory Animal Resource & Research Center > 1. Journal Articles
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