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

H. M. Kim, S. J. Oh, S. K. Park, Gyoonhee Han, K. Kim, K. S. Lee, J. S. Kang, M. Nam, K. Lee

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)281-293
Number of pages13
JournalXenobiotica
Volume38
Issue number3
DOIs
Publication statusPublished - 2008 Mar 1

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Lactams
Histone Deacetylase Inhibitors
Liver Microsomes
Metabolism
Liver
Serum
Uridine Diphosphate Glucuronic Acid
NADP
Hydroxamic Acids
N-hydroxy-3-(2-oxo-1-phenethyl-1,2,5,6-tetrahydropyridin-3-yl)propanamide
In Vitro Techniques
Glucuronides
Biotransformation
Metabolites
Carboxylic Acids
Cytochrome P-450 Enzyme System
Rats
Oxidation
Molecules

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis

Cite this

Kim, H. M. ; Oh, S. J. ; Park, S. K. ; Han, Gyoonhee ; Kim, K. ; Lee, K. S. ; Kang, J. S. ; Nam, M. ; Lee, K. / In vitro metabolism of KBH-A40, a novel δ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum. In: Xenobiotica. 2008 ; Vol. 38, No. 3. pp. 281-293.
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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.",
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In vitro metabolism of KBH-A40, a novel δ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum. / Kim, H. M.; Oh, S. J.; Park, S. K.; Han, Gyoonhee; Kim, K.; Lee, K. S.; Kang, J. S.; Nam, M.; Lee, K.

In: Xenobiotica, Vol. 38, No. 3, 01.03.2008, p. 281-293.

Research output: Contribution to journalArticle

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T1 - In vitro metabolism of KBH-A40, a novel δ-lactam-based histone deacetylase (HDAC) inhibitor, in human liver microsomes and serum

AU - Kim, H. M.

AU - Oh, S. J.

AU - Park, S. K.

AU - Han, Gyoonhee

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AU - Kang, J. S.

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AU - Lee, K.

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N2 - 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.

AB - 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.

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