In vitro characterization of the oxidative cleavage of the octyl side chain of olanexidine, a novel antimicrobial agent, in dog liver microsomes

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 olanexidi ne to C-C bond cleavage metabolites. Olanexidine was initially biotransform ed to monohydroxylated metabolite 2-octanol (DM-215), and DM-215 was subseq uently oxidized to diol derivatives threo-2,3-octandiol (DM-221) and erythr o-2,3-octandiol (DM-222). Diols were further biotransformed to a ketol deri vative and C-C bond cleavage metabolite (DM-210, hexanoic acid derivative), an in vivo end product, in the incubation with dog liver microsomes. The f ormations of DM-215, DM-221, DM-222, and DM-210 followed Michaelis-Menten k inetics, and Eadie-Hofstee analysis of the metabolite formation activity co nfirmed single-enzyme Michaelis-Menten kinetics. The K-m and V-max values f or the formation of DM-210 appeared to be 2.42 muM and 26.6 pmol/min/mg in the oxidation of DM-221 and 2.48 muM 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 re actions was essentially the same with either DM-221 or DM-222 as substrate. These oxidative reactions were significantly inhibited by quinidine, a sel ective inhibitor of CYP2D subfamilies, indicating the metabolic C-C bond cl eavage 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 d rugs or endogenous compounds possessing aliphatic chains.