Predicting the oral bioavailability of 19-nortestosterone progestins in vivo from their metabolic stability in human liver microsomal preparations in vitro.

It was the aim of this study to investigate whether assessment of the metabolic stability of selected progestins of the 19-nortestosterone type in human microsomal liver preparations was a suitable approach to predict the oral bioavailability of these drugs in humans. The Michaelis-Menten parameters Vmax and KM,app for norethisterone, levonorgestrel, gestodene, desogestrel, 3-keto-desogestrel, norgestimate, and dienogest were determined in in vitro incubations with human liver microsomes. Using these data, both the in vitro intrinsic clearance (CLint) and, after application of a suitable scaling factor, the scaled in vivo CLint were calculated. For progestins for which human in vivo data were available, the in vitro results were correlated with in vivo CLint values and oral bioavailability. A comparison of the scaled in vivo CLint values with the corresponding in vivo CLint values showed a reasonable correlation, although the latter values were generally approximately 2-fold higher than the former. Excluding desogestrel, which is subject to substantial intestinal metabolism in vivo, there was a linear relationship (r = -0.986) between increasing in vitro CLint values for the progestins and decreasing bioavailability in vivo. Other methods of assessing the metabolic stability of the progestins in vitro, such as evaluation of metabolic half-lives at single initial concentrations, showed either no correlation or a less satisfactory correlation with bioavailability data.