title: Stereoselective reductive metabolism of metyrapone and inhibitory activity of metyrapone metabolites, metyrapol enantiomers, on steroid 11 beta-hydroxylase in the rat.
abstract: 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 11 beta-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 11 beta-hydroxylase and each enantiomer of metyrapol showed similar inhibitory activity on the rat adrenal steroid 11 beta-hydroxylase. These results indicate there is an insignificant difference in the inhibitory effects on steroid 11 beta-hydroxylase of metyrapol enantiomers, and that the inhibitory effects of metyrapol may be involved in the pharmacological activity of metyrapone in vivo.
authors.affiliation: Department of Pharmaceutics, Kobe Pharmaceutical University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nagamine
authors.forename: E
authors.initials: E
authors.lastname: Horisaka
authors.forename: Y
authors.initials: Y
authors.lastname: Fukuyama
authors.forename: K
authors.initials: K
authors.lastname: Maetani
authors.forename: R
authors.initials: R
authors.lastname: Matsuzawa
authors.forename: S
authors.initials: S
authors.lastname: Iwakawa
authors.forename: S
authors.initials: S
authors.lastname: Asada
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008797:Metyrapone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C002196:metyrapol; D013252:Steroid 11-beta-Hydroxylase; D008797:Metyrapone