Metabolism of 11-oxygenated steroids. 3. Some 1-dehydro and 9α-fluoro steroids

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Abstract
The metabolism of 9[alpha]-fluorocortisol, 9[alpha]-fluorocortisone, prednisone and 9[alpha]-fluoroprednisone 21-acetate was investigated after their oral administration to young male subjects, with special reference to the oxidation-reduction of the 11-oxygen function of these steroids. The excretion of the metabolites of endogenously secreted steroids was also measured during the experiments, and the concentrations of cortisol and of the administered analogues in the plasma were measured at the same time. Both the 9[alpha]-fluoro-ll-ketones gave rise to a greater proportion of the related 11[beta]-ols in the plasma, shortly after administration, than was found with the halogen-free parent steroids. 9[alpha]-Fluorocortisol and 9[alpha]-fluorocortisone gave rise to a set of metabolites analogous to those given by cortisol and cortisone as far as reduction of the A-ring structures, and reduction and removal of the side chains were concerned. The most striking finding, however, was that the expected 11-ketones were almost completely absent from the urine of the subject given 9[alpha]-fluorocortisone, and undetectable in the urine of the subject given 9[alpha]-fluorocortisol. A similar difference was found between the metabolites of 9[alpha]-fluoroprednisone 21-acetate and those of prednisone itself. The ring-A-saturated metabolites of 9[alpha]-fluorocortisol and 9[alpha]-fluorocortisone included a far greater proportion of 5[alpha]-(H) steroids than was found with the halogen-free parent steroids. Similarly, the metabolism of endogenous cortisol was altered in the same direction during the experiments, resulting in considerably increased relative amounts of allotetrahydrocortisol and 11[beta]-hydroxy-androsterone in the urine. It is suggested that these results can be explained in terms of 2 probable mechanisms. First, the negative inductive effect of the fluorine atom causes an increase in the stability of the 11[beta]-ol relative to the 11-ketone resulting in a purely thermodynamic effect increasing the rate of reduction and decreasing the rate of oxidation in the redox reaction 11[beta] = 11-ketone. Secondly, it seems probable that certain 9[alpha]-fluoro-11[beta]-hydroxy steroids inhibit the oxidative direction of the reaction and may also selectively inhibit 5[beta]-reduction of the 4,5-double bond in [image] 4-3-oxo steroids. A comparison with results obtained in vitro suggests that these results are largely or entirely due to differences in the hepatic transformation of these steroids and not to other factors such as their mode of absorption or distribution. The results add further confirmation to earlier suggestions that the biological actions of 11-oxygenated steroids depend on the interaction of the 11[beta]-hydroxy form with tissue receptors and not on the redox reaction at CIII itself, except in so far as the latter indirectly affects the proportion of 11[beta]-ol and 11-ketone that is available to the tissues.