Potency and pharmacokinetics of gestagens

Serum concentrations of gestagens were compared after single doses and after multiple doses (steady-state conditions) of four widely used oral contraceptives containing norethisterone (NET), levonorgestrel (LNG), desogestrel (DSG) and gestodene (GSD). There were marked differences among the gestagens with respect to the serum concentrations. Under steady-state conditions 12 h after dosing, the relative concentrations were approximately GSD, 4.5:DSG, 1:LNG, 1:NET, 2 compared to ratios of 1:2:2:13.3, respectively, for dose. Thus, there was no correlation between serum concentration and dose. These differences in serum concentrations are determined by the different pharmacokinetic behaviour of the gestagens, which in turn is largely determined by their binding to serum proteins. Calculations suggest that the concentrations of unbound gestagen in serum, and hence probably also at the target organ, are similar (about 35 pg/ml) for LNG, DSG and GSD but may be higher (up to 60 pg/ml) for NET whose half-life of elimination is about half that of the other three gestagens. Measurement of the serum total concentration is unlikely to correlate with their pharmacological activity. A further complication is the multiplicity of pharmacological effects elicited by the gestagens and each of these effects is likely to have its own dose-response relationship.