Dexamethasone metabolism in vitro: species differences.
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.
Tomlinson
E S
ES
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Maggs
J L
JL
Park
B K
BK
Back
D J
DJ
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism* / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism*; D005260:Female; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013045:Species Specificity
D000893:Anti-Inflammatory Agents; D000935:Antifungal Agents; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006034:Glycyrrhetinic Acid; D007654:Ketoconazole