Pharmacokinetics of norethisterone in humans

The pharmacokinetics of a dose of 1mg norethisterone administered with 50 micrograms ethynyloestradiol was studied in 83 subjects. The dose was rapidly absorbed and there were wide variations in the serum NET concentrations at any particular time after dosing; the concentrations at 24 h varied from 100 to 1700 pg/ml. There was a significant negative correlation between the serum NET concentration and the time after dosing in all women. There were large inter-subject variations in the pharmacokinetic parameters, the elimination half-life and bioavailability showing 3- and 5- fold variability, respectively. Mean values for the parameters were t1/2, 7.6 h; bioavailability, 53.6 ng/ml/h; C max, 4.63 ng/ml; clearance, 22.6 l/h; and Vd 2361. There were a number of statistically significant correlations between the pharmacokinetic parameters and analysis of the correlations suggested that clearance was an important determinant of the bioavailability and of C max whereas the elimination half-life was the determinant of the NET concentration at 24 h. The pharmacokinetics of NET are compared with those of ethynyloestradiol. The wide variation in pharmacokinetics is likely to be important in determining inter-subject variations in efficacy and, particularly, side-effects of oral contraceptives especially now that low-dose formulations are widely used.