Pharmacodynamics and Pharmacokinetics of Synthetic Mineralocorticoids and Glucocorticoids: Receptor Transactivation and Prereceptor Metabolism by 11β-hydroxysteroid-dehydrogenases

Abstract

Glucocorticoid (GC) and mineralocorticoid (MC) action in target tissues is determined by prereceptor metabolism by 11beta-hydroxysteroid-dehydrogenases (HSDs) and receptor transactivation. We characterized these parameters for steroids often used in clinical practice. HSD activity was examined in human liver (HSD1) and kidney microsomes (HSD2) and in CHO cells stably transfected with both enzymes. GC and MC transcriptional activity was tested by luciferase assay in CV-1 cells transfected with human GC or MC receptor expression vectors. The 11-hydroxy-group is necessary for GC and MC receptor transactivation. As HSD2 oxidizes 11-hydroxysteroids to inactive 11-dehydrosteroids, GC and MC activity in HSD2-expressing tissues (kidney, colon) is regulated by this enzyme. As 9alpha-fluorination (such as in 9alpha-fluorocortisol) decreases oxidation by HSD2 and increases both GC and MC receptor transactivation, this modification leads to optimal, but non-selective transactivation of both receptors. Increased GC receptor and decreased MC receptor transactivation leading to more selective GC activity is reached using the following substituents: 16beta-methyl (in betamethasone), 16alpha-methyl (in dexamethasone) and triangle up 1-dehydro-configuration (in prednisolone). Whereas the modifications in position 16 decrease oxidation by HSD2, the triangle up 1-dehydro-configuration increases HSD2-activity leading to an enhanced inactivation of prednisolone compared to all other steroids. 9alpha-fluorocortisol, the most frequently used substance for MC-substitution, seems to be the best choice of available steroids for this purpose. Whereas GC selectivity can be improved by hydrophobic substituents in position 16 and the triangle up 1-dehydro-configuration, maximal GC activity needs additional fluorination in position 9alpha (such as in dexamethasone). For GC therapy directed to HSD2-expressing organs, widely used prednisolone does not seem to be the optimal recommendation.

Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency

“…Interestingly, when the endogenous glucocorticoid, cortisol (hydrocortisone), is compared with prednisolone at the isolated human glucocorticoid receptor (GR), the transactivation activity of prednisolone is 1.7-fold higher than that of hydrocortisone (8, 9). However, the biological effect of prednisolone is usually represented as 4-fold that of hydrocortisone.…”

Determination of unbound prednisolone, prednisone and cortisol in human serum and saliva by on‐line solid‐phase extraction liquid chromatography tandem mass spectrometry and potential implications for drug monitoring of prednisolone and prednisone in saliva

“…11 β ‐HSD‐2 converts prednisolone into prednisone, while its counterpart 11 β ‐HSD‐1 performs the reverse step. 11 β ‐HSD‐1 facilitates GC‐access to the glucocorticoidreceptor and is present in tissues throughout the body (Czock et al ., ; Diederich et al ., ). In contrast, 11 β ‐HSD‐2 is found predominantly at mineralocorticoid target sites, such as the kidney, colon, placenta and salivary glands (Czock et al ., ; Kataoka et al ., ; Diederich et al ., ; Gross and Cidlowski, ).…”

“…11 β ‐HSD‐1 facilitates GC‐access to the glucocorticoidreceptor and is present in tissues throughout the body (Czock et al ., ; Diederich et al ., ). In contrast, 11 β ‐HSD‐2 is found predominantly at mineralocorticoid target sites, such as the kidney, colon, placenta and salivary glands (Czock et al ., ; Kataoka et al ., ; Diederich et al ., ; Gross and Cidlowski, ). A crucial finding here was that, when concentrations of prednisolone and prednisone in saliva were added up, they showed excellent correlation with the addition sum of prednisolone and prednisone in ultrafiltrate (Fig.…”

PSA response following the ‘steroid switch’ in patients with castration‑resistant prostate cancer treated with abiraterone: A case report

“…Pharmacokinetic differences between dexamethasone and prednisolone might explain the mechanisms. The half-life of dexamethasone is longer, which may produce a more effective suppression of ACTH and higher antitumoral activity than prednisolone (16). Dexamethasone is thought to be a more potent agent than prednisolone due to its stronger glucocorticoid activity and lower mineralocorticoid activity (17).…”