Abstract
The metabolism of 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB-2045), a new potent biguanide antiseptic, was investigated using rat and dog liver preparations to elucidate the mechanism of OPB-2045 metabolite formation, in which the octyl side chain is reduced to four, five, or six carbon atoms. Chemical structures of metabolites were characterized by 1H NMR, fast atom bombardment/mass spectrometry, and liquid chromatography/electrospray ionization-tandem mass spectrometry. Three main metabolites were observed during incubation 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-octandiol (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 required NADPH as a cofactor and were significantly inhibited by the various inhibitors of cytochrome P450 (i.e., CO,n-octylamine, SKF 525-A, metyrapone, and α-naphthoflavone). The results indicate that the degraded products of OPB-2045 are produced by C-C bond cleavage after monohydroxylation, dihydroxylation, and ketol formation at the site of the octyl side chain with possible involvement of cytochrome P450 systems. This aliphatic C-C bond cleavage by sequential oxidative reactions may play an important role in the metabolism of other drugs or endogenous compounds that possess aliphatic chains.
Footnotes
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Send reprint requests to: Ken Umehara, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463–10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan. E-mail:k_umehara{at}research.otsuka.co.jp
- Abbreviations used are::
- OPB-2045
- 1-(3,4-dichlorobenzyl)-5-octylbiguanide monohydrochloride hemihydrate
- DM-210
- 6-[5-(3,4-dichlorobenzyl)-1-biguanidino] hexanoic acid
- DM-212
- 4-[5-(3,4-dichlorobenzyl)-1-biguanidino] butanoic acid
- DM-213
- 5-[5-(3,4-dichlorobenzyl)-1-biguanidino] pentanoic acid
- M-1 (DM-215)
- 8-[5-(3,4-dichlorobenzyl)-1-biguanidino]-2-octanol
- M-2 (DM-218)
- 8-[5-(3,4-dichlorobenzyl)-1-biguanidino]-3-octanol
- M-3 (DM-217)
- 8-[5-(3,4-dichlorobenzyl)-1-biguanidino]-4-octanol
- M-4 (DM-219)
- 8-[5-(3,4-dichlorobenzyl)-1-biguanidino]-2-octanone
- M-5 (DM-221)
- threo-8-[5-(3,4-dichlorobenzyl)-1-biguanidino]-2,3-octandiol
- M-6 (DM-222)
- erythro-8-[5- (3,4-dichlorobenzyl)-1-biguanidino]-2,3-octandiol
- M-7 (DM-220)
- 8-[5-(3,4-dichlorobenzyl)-1-biguanidino]-1,2-octandiol
- S9
- 9000g supernatant fraction of liver homogenate
- FAB
- fast atom bombardment
- MS
- mass spectrometry
- LC/ESI-MS/MS
- liquid chromatography/electrospray ionization-tandem mass spectrometry
- Received November 19, 1999.
- Accepted November 19, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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