Formation of reductive metabolite, 2-sulfamoylacetylphenol, from zonisamide in rat liver microsomes.
Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was metabolized to its reductive product, 2-sulfamoylacetylphenol, in rat liver microsomes under anaerobic conditions. The rate of NADPH-dependent reaction was much more rapid than that of NADH-dependent reaction. Furthermore, synergistic effect of NADH on NADPH-dependent reaction was not observed. The optimal formation of 2-sulfamoylacetylphenol from zonisamide in the presence of NADPH was observed around pH 7.0. Cimetidine showed an inhibitory effect on the formation of 2-sulfamoylacetylphenol in a dose-dependent manner. The reductive metabolism of zonisamide was almost completely inhibited by carbon monoxide, and was increased by pretreatment of rats with phenobarbital and pregnenolone 16 alpha-carbonitrile but not by pretreatment with ethanol, 3-methylcholanthrene and imidazole. These results suggest that phenobarbital- and pregnenolone 16 alpha-carbonitrile-inducible form(s) of cytochrome P-450 is responsible for the reductive metabolism of zonisamide to 2-sulfamoylacetylphenol in rat liver microsomes.
Nakasa
H
H
Hospital Pharmacy, Chiba University Hospital, Inohana, Japan.
Komiya
M
M
Ohmori
S
S
Kitada
M
M
Rikihisa
T
T
Kanakubo
Y
Y
D000693:Anaerobiosis; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism; D002248:Carbon Monoxide / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010636:Phenols / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013449:Sulfonamides / Q000378:metabolism*; D000078305:Zonisamide
D000927:Anticonvulsants; D007555:Isoxazoles; D010636:Phenols; D013449:Sulfonamides; D000078305:Zonisamide; D009249:NADP; C077805:2-sulfamoylacetylphenol; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System