Alclofenac epoxide

In contrast, a number of alkene epoxides (10.3) are chemically quite stable, i.e., intrinsically less reactive than arene oxides. Examples of epoxide metabolites that have proven to be stable enough to be isolated in the absence of degrading enzymes include 1,2-epoxyoctane (10.4), 1,2-epoxycyclohex-ane (10.5), 1-phenyl-1,2-epoxy ethane (styrene oxide, 10.6), and cis- 1,2-diphenyl-1,2-epoxyethane (cfv-stilbene oxide, 10.7) [12], The same is true of alclofenac epoxide (10.8), hexobarbital epoxide (10.9), and a few other epoxides of bioactive compounds. 

Mercier M, Poncelet F, de Meester C, McGregor DB, Willins MJ, Leonard A, Fabry L. In vitro and in vivo studies on the potential mutagenicity of alclofenac, dihydrox-yalclofenac and alclofenac epoxide. J Appl Toxicol 1983 3(5) 230—236. 

J. A. Slack, A. W. Ford-Hutchinson, M. Richold, B. C. K. Choi, Some Biochemical and Pharmacological Properties of an Epoxide Metabolite of Alclofenac , Chem.-Biol. Interact. 1981, 34, 95 - 107. 

Olefins can also undergo CYP-catalyzed epoxidation the NSAID alclofenac, which has been withdrawn from the clinic due to many cases of skin rash and hepatotoxicity, serves as a noteworthy example of this phenomenon. The epoxide metabolite of alclofenac (Scheme 14) has been detected in human urine as a stable metabolite (Slack and Ford-Hutchinson, 1980). The synthetic standard of the epoxide metabolite is a mutagen in the Salmonella Ames test and forms conjugates with sulfydryl nucleophiles (Slack et ah, 1981 Mercier et ah, 1983). The observation that the epoxide metabolite exhibits a NADPH-independent but... 

Brown LM, Ford-Hutchinson AW. The destruction of cytochrome P-450 by alclofenac Possible involvement of an epoxide metabolite. Biochem Pharmacol 1982 31 (2) 195-199. 

Slack JA, Ford-Hutchinson AW, Richold M, Choi BC. Determination of a urinary epoxide metabolite of alclofenac in man. Drug Metab Dispos 1980 8(2) 84—86. 

Determination of a Urinary Epoxide Metabolite of Alclofenac in Man Drug Metab. Dispos. 8(2) 84-86... 

Cautreels, W., and Roncucci, R. Determination of a Trace Epoxide Metabolite of Alclofenac in Man Adv. Mass Spectrom. 8B 1280-1282 (1980) CA 94 95555n... 

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