J Pharmacol Exp Ther. 1996 Apr;277(1):105-12.  

Dexamethasone metabolism by human liver in vitro. Metabolite identification and
inhibition of 6-hydroxylation.

Gentile DM, Tomlinson ES, Maggs JL, Park BK, Back DJ.

Department of Pharmacology & Therapeutics, University of Liverpool, United
Kingdom.

The metabolism of the synthetic glucocorticoid dexamethasone in human liver
microsomal incubations has been studied. Metabolites were analyzed by
radiometric high-performance liquid chromatography and were identified by
liquid-chromatography-mass spectrometry; in addition, the major metabolite
6beta-hydroxydexamethasone was identified by cochromatography with a chemically
synthesized standard. A total of 17 human livers were used in this study and the
following metabolites were identified: 6beta-hydroxydexamethasone, 6
alpha-hydroxydexamethasone, 6-hydroxy-9 alpha-fluoro-androsta-1,4-diene-11
beta-hydroxy-16 alpha-methyl-3,17-dione (6-hydroxy-9 alpha-F-A) and 9
alpha-fluoro-androsta-1,4-diene-11 beta-hydroxy-16 alpha-methyl-3,17-dione (9
alpha-F-A). Dexamethasone underwent side-chain cleavage to form 9 alpha-F-A.
This metabolite was then a substrate for 6-hydroxylation. There was considerable
interindividual variability in metabolic profiles. Mean (+/-S.D.) K(m) values
for 6 beta- and 6 alpha-hydroxydexamethasone formation were 23.2 +/- 3.8 and
25.6 +/- 1.6 microM (n = 4), respectively. The corresponding V max values were
14.3 +/- 9.9 and 4.6 +/- 3.1 pmol x min(-1) mg protein (-1). Ketoconazole (3
microM) completely inhibited 6 alpha- and 6 beta-hydroxylation, indicating that
formation of both metabolites was catalyzed by CYP3A4. This was confirmed in
studies of correlations between the rate of metabolite formation and the
relative expression of CYP3A4: r = 0.74 for 6 beta-hydroxydexamethasone, P =
.003; r = 0.70 for 6 alpha-hydroxydexamethasone, P = .006. In addition to
ketoconazole, both ellipticine and gestodene caused marked inhibition of
6-hydroxylation. Ellipticine is clearly not a selective CYP1A inhibitor as has
been stated previously. However, furafylline (CYP1A inhibitor), tolbutamide
(CYP2C substrate), and sulfaphenazole (CYP2C inhibitor) were essentially
noninhibitory. The relatively simple metabolic profile of dexamethasone compared
to other steroids may point to this being a potentially useful in vivo probe for
CYP3A4 in humans.

PMID: 8613906 [PubMed - indexed for MEDLINE]