Oxidative one-carbon cleavage of the octyl side chain of olanexidine, a novel antimicrobial agent, in dog liver microsomes.
1. The oxidative one-carbon cleavage reaction in the octyl side chain of olanexidine [1-(3,4-dichlorobenzyl)-5-octylbiguanide], a new potent biguanide antiseptic, was characterized in dog liver microsomes. 2. Olanexidine was initially biotransformed to a monohydroxylated metabolite, 8-[5-(3,4-dichlorobenzyl)-1-biguanidino]-2-octanol (DM-215), and DM-215 was subsequently oxidized to the diol derivative, 8-[5-(3,4-dichlorobenzyl)-1-biguanidino]-1,2-octandiol (DM-220). DM-220 was further biotransformed to 2-hydroxy aldehyde derivative, 2-hydroxy carboxylic acid derivative, and an oxidative C-1-C-2 bond cleavage metabolite, 7-[5-(3,4-dichlorobenzyl)-1-biguanidino] heptanoic acid [DM-223 (C7), a seven-carbon chain derivative], after incubation with dog liver microsomes. 3. DM-223 formation required NADPH as a cofactor and was inhibited by quinidine and quinine, relatively selective inhibitors of CYP2D subfamilies in dogs. 4. The results suggest that the one-carbon fragment of the octyl side chain of olanexidine could be removed by the oxidative C-C bond cleavage with the possible involvement of cytochrome P450 systems such as CYP2D subfamily. This oxidative C-C bond cleavage reaction by cytochrome P450s could play an important role in the removal of one-carbon fragment of other drugs or endogenous compounds containing aliphatic chains.
Umehara
K
K
Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd, Japan. k_umehara@research.otsuka.co.jp
Shimokawa
Y
Y
Koga
T
T
Ohtani
T
T
Miyamoto
G
G
D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001645:Biguanides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization
D000890:Anti-Infective Agents; D001645:Biguanides; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D009249:NADP; C113749:olanexidine; D011803:Quinine; D011802:Quinidine