抗惊厥药物唑尼沙胺（一种1,2 - 苯并异恶唑衍生物）的还原代谢

Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative.

Stiff D D, Robicheau J T, Zemaitis M A

Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh.

Xenobiotica. 1992 Jan;22(1):1-11. doi: 10.3109/00498259209053097.

Abstract

The metabolism of zonisamide in vitro was characterized through aerobic and anaerobic incubations with rat liver subcellular fractions and cultured gastrointestinal microflora. 2. Zonisamide reacted with rat hepatic microsomal cytochrome P-450 and exhibited a Type I binding spectrum. 3. Metabolism of zonisamide in vitro by hepatic subcellular fractions and cultured gastrointestinal flora produced a single metabolite, 2-(sulphamoylacetyl)-phenol (2-SMAP), by reductive cleavage of the 1,2-benzisoxazole ring. 4. The reductive metabolism of zonisamide was primarily mediated by microsomal cytochrome P-450. The soluble fraction enhanced reduction when combined with the microsomal fraction but itself possessed only weak reductive activity. 5. Reduction of zonisamide by the most enzymically active liver fractions required NADPH, was stimulated by FMN and SKF-525A, and was inhibited by CO or air, as well as by n-octylamine. 6. Unlike their involvement in the reduction of numerous nitro, azo, and N-oxide compounds, cultured aerobic and anaerobic intestinal flora were not principally involved in the reduction of zonisamide.

摘要

通过与大鼠肝脏亚细胞组分和培养的胃肠道微生物群进行需氧和厌氧孵育，对唑尼沙胺的体外代谢进行了表征。2. 唑尼沙胺与大鼠肝微粒体细胞色素P-450反应，并呈现出I型结合光谱。3. 肝亚细胞组分和培养的胃肠道菌群在体外对唑尼沙胺的代谢通过1,2-苯并异恶唑环的还原裂解产生单一代谢物2-(氨磺酰乙酰基)-苯酚(2-SMAP)。4. 唑尼沙胺的还原代谢主要由微粒体细胞色素P-450介导。可溶性组分与微粒体组分结合时可增强还原作用，但其本身仅具有较弱的还原活性。5. 酶活性最高的肝脏组分对唑尼沙胺的还原需要NADPH，受FMN和SKF-525A刺激，受CO或空气以及正辛胺抑制。6. 与它们参与多种硝基、偶氮和N-氧化物化合物的还原不同，培养的需氧和厌氧肠道菌群在唑尼沙胺的还原中不起主要作用。