Dexamethasone metabolism in vitro: species differences

J Steroid Biochem Mol Biol. 1997 Jul;62(4):345-52. doi: 10.1016/s0960-0760(97)00038-1.


Dexamethasone (DEX) is extensively metabolized to 6-hydroxyDEX (6OH-DEX) and side-chain cleaved metabolites in human liver both in vitro and in vivo with CYP3A4 responsible for the formation of 6-hydroxylated products. In the present study, the metabolism of [3H]DEX has been examined in the liver fractions from various mammalian species and metabolite profiles compared with those obtained with human liver microsomes. Metabolites were quantified by radiometric high-pressure liquid chromatography (HPLC) and characterized by liquid chromatography-mass spectrometry (LC-MS) and co-chromatography with chemical standards, where available. 6OH-DEX formation was quantified for each species and the inhibitory potency of ketoconazole at 1 and 20 microM determined. Glycyrrhetinic acid, a specific inhibitor of 11-dehydrogenase, was also used to determine the extent of reductive DEX metabolism. Species differences in metabolite profiles obtained from microsomal incubations were both quantitative and qualitative. 6-Hydroxylation was variable (highest in the hamster) and was not always the major route of metabolism, and formation was sex-specific in the rat (male >> female). The inhibition of 6-hydroxylation (CYP3A) by ketoconazole was variable, and indicates that ketoconazole cannot be regarded as a selective inhibitor of CYP3A proteins in all species. Cytosolic incubations produced similar profiles in different species with the formation of a metabolite (M5) which was inhibited by glycyrrhetinic acid and tentatively identified in this study as 11-dehydro-side-chain cleaved DEX (11DH-9alphaF-A). In conclusion, the male rat gave a metabolite profile which was closest to that seen in the human. However, 6-hydroxylation was most extensive in the hamster which may therefore be a suitable model to use for further studies on DEX metabolism by CYP3A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Animals
  • Anti-Inflammatory Agents / metabolism*
  • Anti-Inflammatory Agents / pharmacology
  • Antifungal Agents / pharmacology
  • Chromatography, High Pressure Liquid
  • Cricetinae
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism
  • Dexamethasone / metabolism*
  • Female
  • Glycyrrhetinic Acid / pharmacology
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Ketoconazole / pharmacology
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism*
  • Mixed Function Oxygenases / metabolism
  • Rabbits
  • Rats
  • Species Specificity*


  • Anti-Inflammatory Agents
  • Antifungal Agents
  • Dexamethasone
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Glycyrrhetinic Acid
  • Ketoconazole