Metabolism-related liabilities of a potent histone deacetylase (HDAC) inhibitor and relevance of the route of administration on its metabolic fate
- 24 June 2009
- journal article
- research article
- Published by Taylor & Francis Ltd in Xenobiotica
- Vol. 39 (10), 722-737
- https://doi.org/10.1080/00498250903082279
Abstract
Compound A [1-methyl-N-{(1S)-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxooctyl}piperidine-4-carboxamide is a potent class I histone deacetylase (HDAC) inhibitor that demonstrated good antiproliferative activity against human tumour cell lines of different origin. This compound showed high in vivo clearance in rats (160 ml min−1 kg−1) due to metabolism. The main metabolite detected in urine after intravenous dosing was characterized as a dihydrohydroxy S-mercapturic acid conjugate. Following oral dosing, however, the mercapturic acid derivative was no longer the main metabolite but the major metabolites were mono- and di-glucuronide conjugates of oxidized species having a mass shift of +34 m/z with respect to the parent. Comparison of plasma concentration after intra-arterial infusion and intravenous infusion and incubation with microsomes from different tissues (liver, kidney, small intestine and lung) in the presence of β-nicotinamide adenine dinucleotide phosphate (NADPH) indicated that the compound was highly cleared by the lung. Oxidation of the naphthalene moiety was demonstrated to be the cause of the high in vivo clearance of compound A and the potential for bioactivation of this group was flagged.Keywords
This publication has 19 references indexed in Scilit:
- Optimization of a series of potent and selective ketone histone deacetylase inhibitorsBioorganic & Medicinal Chemistry Letters, 2008
- VorinostatNature Reviews Drug Discovery, 2007
- Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancerNature Reviews Cancer, 2006
- IN VITRO METABOLISM OF NAPHTHALENE BY HUMAN LIVER MICROSOMAL CYTOCHROME P450 ENZYMESDrug Metabolism and Disposition, 2005
- In Vitro Metabolism ofR(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a Cannabinoid Receptor AgonistDrug Metabolism and Disposition, 2002
- Histone deacetylases and cancer: causes and therapiesNature Reviews Cancer, 2001
- The biotransformation of isoprene and the two isoprene monoepoxides by human cytochrome P450 enzymes, compared to mouse and rat liver microsomesChemico-Biological Interactions, 1996
- Naphthalene metabolism by human lung microsomal enzymesToxicology, 1986
- Noncompartmental Determination of the Steady‐State Volume of DistributionJournal of Pharmaceutical Sciences, 1979
- Arene oxides and the NIH shift: The metabolism, toxicity and carcinogenicity of aromatic compoundsCellular and Molecular Life Sciences, 1972