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标题：Stereoselective Reductive Metabolism of Metyrapone and Inhibitory Activity of Metyrapone Metabolites, Metyrapol Enantiomers, on Steroid 11β-Hydroxylase in the Rat
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作者：Sachiko NAGAMINE ; Eri HORISAKA ; Yukari FUKUYAMA 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1997
卷号：20
期号：2
页码：188-192
DOI：10.1248/bpb.20.188
出版社：The Pharmaceutical Society of Japan
摘要：Pharmacokinetics of metyrapone and metyrapol enantiomers was studied in the rat to determine the stereoselective reductive metabolism of metyrapone. The HPLC method using a chiral column was developed for the stereoselective analysis of metyrapol enantiomers in rat plasma. The AUC ratio of (-)- and (+)-metyrapol appeared in rat plasma after i.v. administration of metyrapone was about 3 : 1. The interconversion of (-)- or (+)-metyrapol to its antipode was negligible, and the reverse reaction from metyrapol to metyrapone was insignificant. There were similar kinetic parameters of (-)-metyrapol to those of (+)-metyrapol after i.v. administration of racemic metyrapol. These results indicate metyrapone displays product-stereoselective reductive metabolism in the rat. The inhibition of steroid 11β-hydroxylase by metyrapone, racemic metyrapol, (-)-metyrapol or (+)-metyrapol was analyzed in rat adrenal homogenates. Metyrapol was equally as potent as metyrapone in the inhibition of steroid 11β-hydroxylase and each enantiomer of metyrapol showed similar inhibitory activity on the rat adrenal steroid 11β-hydroxylase. These results indicate there is an insignificant difference in the inhibitory effects on steroid 11β-hydroxylase of metyrapol enantiomers, and that the inhibitory effects of metyrapol may be involved in the pharmacological activity of metyrapone in vivo.
关键词：metyrapone;enantiometric metabolite;stereoselective reduction;pharmacokinetics;rat adrenal;11β-hydroxylase