Invitro and Invivo Inhibition of Metyrapone metabolism by Glycyrrhetinic Acid in Male Wistar Rats

Objectives: We investigated the inhibitory effect of glycyrrhetinic acid (GA), an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, on the reductive metabolism of metyrapone (MP) in an invitro study, and the effect of the co-administration of GA on the pharmacokinetics of MP and its metabolites in rats. Methods: High-performance liquid chromatography was used to determine the metabolic activities of MP in the liver and testis and the plasma concentrations of MP and its metabolites after MP with or without a GA dose to rats. Results: GA strongly inhibited the reduction of MP to metyrapol(MPOL) in the microsomal and mitochondrial fractions of both the tissues in a dose-dependent manner. When GA was co-administrated, the plasma levels of MPOL and MPOL N-oxide II (MPOL NOII) were lower than those of MP alone, while the levels of MP and MP NOII were higher than those of MP alone. Conclusion: The in vitro GA inhibition suggests that the reduction of MP in the rat liver and testis is catalyzed by 11β-HSD1. The coadministration of GA modulated the plasma pharmacokinetics of MP, MPOL, MP NOII and MPOL NOII, suggesting that the changes in the pharmacokinetics were caused by the inhibition of 11β-HSD1 invivo.