Oxidative cleavage of the octyl side chain of 1-(3,4-dichlorobenzyl)-5octylbiguanide (OPB-2045) in rat and dog liver preparations

The metabolism of 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB-2045), a new potent biguanide antiseptic, was investigated using rat and dog liver prep arations to elucidate the mechanism of OPB-2045 metabolite formation, in wh ich the octyl side chain is reduced to four, five, or six carbon atoms. Che mical structures of metabolites were characterized by H-1 NMR, fast atom bo mbardment/mass spectrometry, and liquid chromatography/electrospray ionizat ion-tandem mass spectrometry. Three main metabolites were observed during i ncubation of OPB-2045 with rat liver S9: 2-octanol (M-1), 3-octanol (M-2), and 4-octanol (M-3). In the incubation of OPB-2045 with dog liver S9, eight metabolites were observed, seven of which being M-1, M-2, M-3, 2-octanone (M-4), threo-2,3-octandiol (M-5), erythro-2,3-octandiol (M-6), and 1,2-octa ndiol (M-7). M-5 and M-6 were further biotransformed to a ketol derivative and C-C bond cleavage metabolite (hexanoic acid derivative), an in vivo end product, in the incubation with dog liver microsomes. The reactions requir ed NADPH as a cofactor and were significantly inhibited by the various inhi bitors of cytochrome P450 (i.e., CO, n-octylamine, SKF 525-A, metyrapone, a nd alpha-naphthoflavone). The results indicate that the degraded products o f OPB-2045 are produced by C-C bond cleavage after monohydroxylation, dihyd roxylation, and ketol formation at the site of the octyl side chain with po ssible involvement of cytochrome P450 systems. This aliphatic C-C bond clea vage by sequential oxidative reactions may play an important role in the me tabolism of other drugs or endogenous compounds that possess aliphatic chai ns.