Impaired renal 11 beta-oxidation of 9 alpha-fluorocortisol: an explanation for its mineralocorticoid potency.

Abstract

9 alpha-Fluorocortisol (9 alpha FF) is about 200 times more potent as a mineralocorticoid than cortisol (F) in man, although it binds with the same affinity as F and aldosterone to the human mineralocorticoid receptor. The low mineralocorticoid activity of F has been shown to be due to its rapid conversion by the kidney to cortisone (E), which does not bind to the receptor. Therefore, we compared the conversion of F to E with that of 9 alpha FF to 9 alpha-fluorocortisone (9 alpha FE) by 11-hydroxysteroid dehydrogenases in man in vivo and in vitro. Single oral doses of 9 alpha FF, 9 alpha FE, and F were given to normal males, and the excretion of free 9 alpha FF, 9 alpha FE, F, and E was measured in urine. Human kidney and liver slices were incubated with unlabeled steroids, and the free 11-hydroxy- and 11-oxosteroids were quantitated after high performance liquid chromatography separation by UV absorption. Oral F (5 mg) is excreted 70% as free E and 30% as free F (percentage of free steroids only). Oral 9 alpha FF (5 mg) is excreted 90% as free 9 alpha FF and 10% as free 9 alpha FE. Free 9 alpha FF excretion is 14 times greater than that of F after ingesting an identical dose. Oral 9 alpha FE (4 mg) is also excreted 90% as 9 alpha FF and 10% as 9 alpha FE. Kidney slices convert F much faster to E than 9 alpha FF to 9 alpha FE. The conversion of 9 alpha FE to 9 alpha FF is, on the contrary, much faster than that of E to F. Thus, the equilibrium of the reaction is on the 11-oxo side for F/E and on the 11-hydroxy side for 9 alpha FF/9 alpha FE. The interconversion of both pairs of steroids is inhibited by glycyrrhetinic acid in a dose-dependent manner. Liver slices do not measurably convert 9 alpha FF to 9 alpha FE, but do rapidly convert 9 alpha FE into 9 alpha FF. Reflecting this negligible conversion of 9 alpha FF to 9 alpha FE and the low plasma-protein binding of 9 alpha FF, free urinary 9 alpha FF excretion is much higher than that of F after the same oral dose.(ABSTRACT TRUNCATED AT 400 WORDS)

Selective inhibition of human type 1 11β‐hydroxysteroid dehydrogenase by synthetic steroids and xenobiotics

“…Depending on their chemical structure, they display pharmacological profiles different from those of the naturally occurring glucocorticoids. This can be explained in part by their different metabolic properties, as for example in the case of 9α‐fluorinated GCs [22, 23]. We therefore studied the metabolism and inhibitor characteristics of commonly used synthetic systemic and topical GCs with the recombinant type 1 enzyme, allowing us to draw conclusions concerning the active site architecture.…”

Urinary free cortisone and the assessment of 11β‐hydroxysteroid dehydrogenase activity in man

“…The aim of this study was to assess the effect of hydrocortisone replacement on cardiovascular function in patients with hypopituitarism and its results have been reported (Dunne et al, 1995). All patients were fully replaced, where appropriate, with other endocrine drugs (thyroxine, sex steroids and DDAVP), but no patient received GH or fludrocortisone, each of which may alter cortisol metabolism (Weaver et al, 1994;Oelkers et al, 1994). Patients had been taking the above doses of hydrocortisone for at least 3 months prior to the urine collection.…”

11β‐Hydroxysteroid‐dehydrogenase isoforms: tissue distribution and implications for clinical medicine

“…Astonin HR) is used for mineralocorticoid (MC) substitution in patients with Addison's disease. In experiments with human kidney slices, we have shown that its high MC potency compared to unfluorinated cortisol is due to decreased renal oxidation (inactivation) and increased renal reduction of the 11-oxo steroid [40]. As these studies did not prove which isoenzyme was responsible for the unexpected renal reductase activity, we did further experiments with dexamethasone (D), an often used 9␣-fluorinated GC.…”