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H Nakasa, M Komiya, S Ohmori, T Rikihisa, M Kiuchi and M Kitada
Division of Pharmacy, Chiba University Hospital, Faculty of Medicine, Chiba University, Japan.
Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was metabolized to 2-sulfamoylacetylphenol (SMAP) in human liver microsomes under anaerobic conditions. The formation of SMAP was remarkably inhibited by cimetidine, n-octylamine, ketoconazole, and carbon monoxide, indicating that a cytochrome P450 is involved in the metabolism of zonisamide to SMAP in human liver microsomes. The SMAP-producing activity did not correlate with the spectrally determined amount of cytochrome P450. In contrast, the SMAP-producing activity from zonisamide correlated closely with the activity of testosterone 6 beta-hydroxylase (r2 = 0.96) and correlated slightly but significantly with the activity of imipramine 2-hydroxylase (r2 = 0.28), but not with those of aniline hydroxylase (r2 = 0.09) or benzphetamine N-demethylase (r2 = 0.20). In addition, immunoquantitation of cytochrome P450 enzymes in 21 human liver microsomal samples revealed that SMAP formation correlated closely with the amount of P450 3A enzyme and correlated moderately well with that of P450 2D6 but not with that of P450 2C enzyme in human liver microsomes. P450 3A4 exhibited SMAP-producing activity in a reconstituted monooxygenase system. The metabolism of zonisamide to SMAP was almost completely inhibited by anti-P450 3A4 antibody but not by anti-P450 2C9 or anti-P450 2D6 antibodies, suggesting that the amount of P450 3A enzyme may be a major factor influencing the level of metabolism of zonisamide to SMAP in human liver microsomes.
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