FORMATION OF 2-SULPHAMOYLACETYLPHENOL FROM ZONISAMIDE UNDER AEROBIC CONDITIONS IN RAT-LIVER MICROSOMES

1. The antiepileptic agent zonisamide, 1,2-benzisoxazole-3-methanesulp honamide, was metabolized reductively to 2-sulphamoyl-acetylphenol (SM AP) not only under anaerobic conditions but also under aerobic conditi ons in liver microsomes of rat pretreated with phenobarbital or dexame thasone. 2. NADPH was required for the formation of SMAP from zonisami de under aerobic conditions. In addition, the reductive metabolism of zonisamide under these conditions was substantially inhibited by carbo n monoxide, ketoconazole, and cimetidine, known inhibitors of cytochro me P450. 3. The formation of SMAP under aerobic conditions in liver mi crosomes was increased by pretreatment of rat with triacetyloleandomyc in (TAO) and was increased by the treatment of the microsomes with fer ricyanide. 4. These results imply that zonisamide is metabolized reduc tively to SMAP by a cytochrome P450 belonging to the 3A subfamily unde r aerobic conditions as well as anaerobic conditions.