Metabolism-related liabilities of a potent histone deacetylase (HDAC) inhibitor and relevance of the route of administration on its metabolic fate.
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 beta-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.
Fonsi
M
M
Department of DMPK, IRBM, Merck Research Laboratories, Rome, Italy. massimiliano.fonsi@gmail.com
Fiore
F
F
Jones
P
P
Kinzel
O
O
Laufer
R
R
Rowley
M
M
Monteagudo
E
E
D000818:Animals; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004333:Drug Administration Routes; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000494:pharmacology; D009281:Naphthalenes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
C546058:1-methyl-N-((1S)-1-(5-(2-naphthyl)-1H-imidazol-2-yl)-7-oxooctyl)piperidine-4-carboxamide; D056572:Histone Deacetylase Inhibitors; D007093:Imidazoles; D009281:Naphthalenes; D010880:Piperidines; D009249:NADP; D003577:Cytochrome P-450 Enzyme System