Metabolism of Synthetic Corticosteroids by 11β-hydroxysteroid-Dehydrogenases in Man

Abstract The presence of an 11β-hydroxyl group is essential for the anti-inflammatory and immunosuppressive effects of glucocorticoids. Interconversion of the 11β-hydroxyl into the corresponding 11β-keto group and vice versa by 11β-hydroxysteroid-dehydrogenases (11β-HSD) may thus play a pivotal role in the efficacy of these steroids. Therefore, we have compared the metabolism of the endogenous glucocorticoid cortisol (F) with that of synthetic 9α-fluorinated steroids by 11β-HSDs in humans in vivo and in vitro. Whereas 30% of the free steroids in urine after oral administration of 5 mg of F is F itself and 70% the inactive keto-product cortisone (E), the urinary excretion of an identical dose of oral 9α-fluorocortisol (9αFF) is 90% 9αFF and 10% inactive 9α-fluorocortisone (9αFE). Kidney slices similarly convert F much faster to E than 9αFF to 9αFE; conversely, renal 11β-reduction of 9αFE to 9αFF is much more effective than that of E to F. Kinetic analyses in human kidney cortex microsomes prove that the preference of fluorinated steroids for reduction in human kidney slices is catalyzed by 11β-HSD type II: the NADH-dependent conversion of 11-dehydro-dexamethasone (DH-D), another fluorinated steroid, to dexamethasone (D) is very effective (high affinity, high Vmax), whereas reduction of E to F is very slow. In human liver microsomes (11β-HSD type I), nonfluorinated (E) and fluorinated 11-dehydrosteroids (DH-D) are both reduced to their corresponding active 11-hydroxyderivatives but with a Michaelis–Menten constant about 20-fold higher than for kidney microsomes (11β-HSD-II). Our results suggest that the decreased renal 11β-oxidation of 9α-fluorinated steroids may offer pharmacokinetic advantages for renal immunosuppression. Furthermore, administration of fluorinated 11-dehydrosteroids is a new and exciting idea in glucocorticoid therapy in that small amounts of oral DH-D may pass the liver largely unmetabolized (11β-HSD-I has low affinity for such steroids) and may then be activated to D by high-affinity 11β-HSD-II, thus allowing selective immunosuppression in organs expressing 11β-HSD-II (kidney and colon).