Abstract

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 parametersV_max andK_M,app for norethisterone, levonorgestrel, gestodene, desogestrel, 3-keto-desogestrel, norgestimate, and dienogest were determined in in vitroincubations with human liver microsomes. Using these data, both thein vitro intrinsic clearance (CL_int) and, after application of a suitable scaling factor, the scaled in vivo CL_int were calculated. For progestins for which human in vivo data were available, the in vitro results were correlated with in vivo CL_int values and oral bioavailability. A comparison of the scaled in vivo CL_int values with the correspondingin vivo CL_int 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 CL_int 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.