Oral pharmacokinetics and in-vitro metabolism of metyrapone in male rats.
OBJECTIVE
The purpose of this study was to investigate the pharmacokinetics of a single oral administration of metyrapone (MP) and metabolites produced from it in male Wistar rats, and the major tissues and enzymes involved in the production of the MP metabolites. Furthermore, the MP metabolism in human liver subcellular fractions was compared with that in rats.


METHODS
High-performance liquid chromatography with ultraviolet detection (HPLC-UV) was used to determine the concentrations of MP and its metabolites in plasma and urine after administration, and the production activity of MP metabolites in subcellular fractions of various tissues.


RESULTS
Plasma concentration of MP was rapidly increased and decreased, and the primary metabolite, metyrapol (MPOL), was immediately produced. The production activity of MPOL was substantially inhibited by an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor in the rat and human liver microsomal and mitochondrial fractions. In the liver cytosolic fraction, the activity was inhibited by a carbonyl reductase inhibitor in the humans but not rats.


CONCLUSIONS
In this study, we elucidated the plasma pharmacokinetics of MP and its metabolites in male rats after an oral administration. MPOL is most likely to be produced by 11β-HSD1 in the male rats and humans.
Pre-clinical department, Janssen Pharmaceutical K.K., Chiyoda-ku, Tokyo, Japan.|Nihon Pharmaceutical University, Saitama, Japan.
Hideyuki
H
Murata
Nihon Pharmaceutical University, Saitama, Japan.
Toshiyuki
T
Higuchi
Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan.
Masaki
M
Otagiri
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000494:pharmacology; D000284:Administration, Oral; D000429:Alcohol Oxidoreductases / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000378:metabolism; D017208:Rats, Wistar
C002196:metyrapol; D000429:Alcohol Oxidoreductases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D008797:Metyrapone
11β-hydroxysteroid dehydrogenase 1; metyrapone; microsomal; mitochondrial; oral administration; pharmacokinetics