RT Journal Article
SR Electronic
T1 Predicting the Oral Bioavailability of 19-Nortestosterone Progestins <em>In Vivo</em> from Their Metabolic Stability in Human Liver Microsomal Preparations <em>In Vitro</em>
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1120
OP 1127
VO 26
IS 11
A1 Wilhelm Kuhnz
A1 Hille Gieschen
YR 1998
UL http://dmd.aspetjournals.org/content/26/11/1120.abstract
AB 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 parametersVmax andKM,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 (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 correspondingin 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. The American Society for Pharmacology and Experimental Therapeutics