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Abstract
1. The oxidative one-carbon cleavage reaction in the octyl side chain of olanexidine [l-(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)-l-biguanidino]-2-octanol (DM-215), and DM-215 was subsequently oxidized to the diol derivative, 8-[5-(3,4-dichlorobenzyl)-l-biguanidino]-l,2-octandiol (DM-220). DM-220 was further biotransformed to 2-hydroxy aldehyde derivative, 2-hydroxy carboxylic acid derivative, and an oxidative C-l –C-2 bond cleavage metabolite, 7-[5-(3,4-dichlorobenzyl)-l-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.
This article was downloaded by: [Collard, Jonathan][informa internal users]
On: 30 Ju148180_755239199_713767701ne 2010
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Publisher Informa Healthcare
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London WlT 3JH, UK
This article was downloaded by: [Collard, Jonathan][informa internal users]
On: 30 Ju148180_755239199_713767701ne 2010
Access details: Access Details: [subscription number 755239602]
Publisher Informa Healthcare
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London WlT 3JH, UK