Teitelbaum P J, Chu N I, Cho D, Tökés L, Patterson J W, Wagner P J, Chaplin M D
J Pharmacol Exp Ther. 1981 Jul;218(1):16-22.
Flunisolide (6 alpha-fluoro-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1,4-diene-3,20-dione-16,17-acetonide) was converted to 6 beta,- 11 beta, 16 alpha, 21-pentahydroxypregna-1,4-diene-3,20-dione-16,17-acetonide (6 beta-OH metabolite) by mouse liver microsomes, but no activity was observed with mouse lung, intestine or kidney microsomes. Two additional metabolites of flunisolide also formed by mouse hepatic microsomes were identified by mass spectral analysis to be 11 beta, 16 alpha, 17 alpha,21-tetrahydroxypregna-1,4-diene-3,6,20-trione-16,17-acetonide (6-keto metabolite) and delta 6-flunisolide. The formation of all three metabolites required NADPH, was inhibited by carbon monoxide and was stimulated by pretreating mice with phenobarbital. A time-couse study suggested the 6-keto metabolite was an intermediate in the formation of the 6 beta-OH metabolite. When added to microsomes, the 6-keto metabolite was converted to the 6 beta-OH metabolite by a carbon monoxide-insensitive enzyme. Our results suggest the conversion of flunisolide to the 6 beta-OH metabolite is catalyzed by a multi-enzyme pathway via a stable intermediate, the 6-keto metabolite. The initial reaction which leads to the formation of the 6-keto metabolite is catalyzed by a cytochrome P-450-mediated microsomal monoxygenase(s), but the reduction of the 6-keto metabolite to the 6 beta-OH metabolite is cytochrome P-450-independent.
氟尼缩松（6α-氟-11β,16α,17α,21-四羟基孕甾-1,4-二烯-3,20-二酮-16,17-缩丙酮）经小鼠肝微粒体转化为6β,-11β,16α,21-五羟基孕甾-1,4-二烯-3,20-二酮-16,17-缩丙酮（6β-羟基代谢物），但在小鼠肺、肠或肾微粒体中未观察到活性。通过质谱分析鉴定出另外两种由小鼠肝微粒体形成的氟尼缩松代谢物，分别为11β,16α,17α,21-四羟基孕甾-1,4-二烯-3,6,20-三酮-16,17-缩丙酮（6-酮基代谢物）和δ6-氟尼缩松。这三种代谢物的形成均需要NADPH，受到一氧化碳的抑制，并受到苯巴比妥预处理小鼠的刺激。一项时间进程研究表明，6-酮基代谢物是6β-羟基代谢物形成过程中的中间体。当添加到微粒体中时，6-酮基代谢物通过一种对一氧化碳不敏感的酶转化为6β-羟基代谢物。我们的结果表明，氟尼缩松向6β-羟基代谢物的转化是通过一个多酶途径，经由稳定的中间体6-酮基代谢物催化的。导致6-酮基代谢物形成的初始反应是由细胞色素P-450介导的微粒体单加氧酶催化的，但6-酮基代谢物还原为6β-羟基代谢物的过程不依赖细胞色素P-450。
