Pharmacokinetics of norethisterone in humans.

ABSTRACT

PIP: The pharmacokinetics of a dose of 1 mg norethisterone administered with 50 mcg ethinyl estradiol was studied in 83 subjects. There were marked variations in age, height, and weight between subjects in the 14 centers, but few of the differences were statistically significant. Table 1 shows the mean values for the serum norethisterone (NET) concentration in samples from each center. Variations between the values observed at any particular time both between the subjects recruited in any 1 center and between subjects in different centers were considerable. Considering only mean values, there was a 2-3-fold variation between the centers at any 1 time. Absorption was quick in most of the 83 subjects. The peak serum concentration occurred within 1 hour in 10 women, between 1-2 hours in 47 women, and between 2-4 hours in 25 women. Elimination was slow, and in only 4 of the 83 subjects had the serum NET concentration declined to 100 pg/ml by 24 hours. Thus, in the majority of women, significant concentrations of NET still were present 24 hours after administration of the dose. For the elimination phase (2-24 hours), there was a significant negative correlation between the logarithm of the serum NET concentration and time after administration of the dose, the correlation coefficient being greater than 0.9 in all but 2 of the 83 women. Due to the large inter-subject variation and the small number of subjects studied in each center, few of the correlations between the pharmacokinetic parameters or of the parameters with the ponderal index in each center were significant although in 10 of the 14 centers there was a significant correlation of the serum NET concentration at 24 hours with the elimination half-life. There was a 3-fold variation between the lowest and highest values for the half-life and a 5-fold variation for area under the curve. In no subject were undetectable NET levels reached in less then 20 hours, and only in 18.5% had the levels decrease below 400 pg/ml. In 63% of the women, a time of 30-50 hours was necessary for serum NET levels to become undetectable, but in 22.2% of the subjects detectable levels were still present at more than 50 hours after administration of the dose. The wide variation in pharmacokinetics is likely to be important in determining inter-subject variations in efficacy and, particularly, side-effects of oral contraceptives.