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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

Authors 

Hwan Mook KimSoo Jin OhSong Kyu ParkG HanK J KimK S LeeJong Soon KangM NamKiho Lee

Publisher 

Informa Healthcare

Issue Date 

2008

Citation 

Xenobiotica, vol. 38, no. 3, pp. 281-293

Keywords 

glucuronidationhistone deacetylasehydrolysishydroxamic acid glucuronidationKBH-A40yl)propanamide]carboxylic acidhistone deacetylase inhibitorkbha 40nicotinamide adenine dinucleotideuridine diphosphate glucuronic acid

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.

ISSN 

0049-8254

Link 

http://dx.doi.org/10.1080/00498250701813222

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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