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The presence of an 11 beta-hydroxyl group is essential for the anti-inflammatory and immunosuppressive effects of glucocorticoids. Interconversion of the 11 beta-hydroxyl into the corresponding 11 beta-keto group and vice versa by 11 beta-hydroxysteroid-dehydrogenase (11 beta-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 9 alpha-fluorinated steroids by 11 beta-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 9 alpha-fluorocortisol (9 alpha FF) is 90% 9 alpha FF and 10% inactive 9 alpha-fluorocortisone (9 alpha FE). Kidney slices similarly convert F much faster to E than 9 alpha FF to 9 alpha FE; conversely, renal 11 beta-reduction of 9 alpha FE to 9 alpha FF 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 11 beta-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 (11 beta-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 (11 beta-HSD-II). Our results suggest that the decreased renal 11 beta-oxidation of 9 alpha-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 (11 beta-HSD-I has low affinity for such steroids) and may then be activated to D by high-affinity 11 beta-HSD-II, thus allowing selective immunosuppression in organs expressing 11 beta-HSD-II (kidney and colon).
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