title: In vitro characterization of the oxidative cleavage of the octyl side chain of olanexidine, a novel antimicrobial agent, in dog liver microsomes.
abstract: The metabolism of olanexidine [1-(3,4-dichlorobenzyl)-5-octylbiguanide], a new potent biguanide antiseptic, was investigated in dog liver microsomes to characterize the enzyme(s) catalyzing the biotransformation of olanexidine to C-C bond cleavage metabolites. Olanexidine was initially biotransformed to monohydroxylated metabolite 2-octanol (DM-215), and DM-215 was subsequently oxidized to diol derivatives threo-2,3-octandiol (DM-221) and erythro-2,3-octandiol (DM-222). Diols were further biotransformed to a ketol derivative and C-C bond cleavage metabolite (DM-210, hexanoic acid derivative), an in vivo end product, in the incubation with dog liver microsomes. The formations of DM-215, DM-221, DM-222, and DM-210 followed Michaelis-Menten kinetics, and Eadie-Hofstee analysis of the metabolite formation activity confirmed single-enzyme Michaelis-Menten kinetics. The K(m) and V(max) values for the formation of DM-210 appeared to be 2.42 microM and 26.6 pmol/min/mg in the oxidation of DM-221 and 2.48 microM and 30.2 pmol/min/mg in the oxidation of DM-222. The intrinsic clearance (V(max)/K(m)) of the C-C bond cleavage reactions was essentially the same with either DM-221 or DM-222 as substrate. These oxidative reactions were significantly inhibited by quinidine, a selective inhibitor of CYP2D subfamilies, indicating the metabolic C-C bond cleavage of the octyl side chain of olanexidine to likely be mediated via the CYP2D subfamily in dog liver microsomes. This aliphatic C-C bond cleavage by cytochrome P450s may play an important role in the metabolism of other drugs or endogenous compounds possessing aliphatic chains.
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Japan. k_umehara@research.otsuka.co.jp
authors.forename: K
authors.initials: K
authors.lastname: Umehara
authors.forename: S
authors.initials: S
authors.lastname: Kudo
authors.forename: Y
authors.initials: Y
authors.lastname: Hirao
authors.forename: S
authors.initials: S
authors.lastname: Morita
authors.forename: T
authors.initials: T
authors.lastname: Ohtani
authors.forename: M
authors.initials: M
authors.lastname: Uchida
authors.forename: G
authors.initials: G
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001645:Biguanides / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction
chemical_list: D000890:Anti-Infective Agents; D001645:Biguanides; D004791:Enzyme Inhibitors; C113749:olanexidine