Metabolism of a new synthetic progestagen, Org 2969, in female volunteers. Pharmacokinetics after an oral dose

Summary

The pharmacokinetics of a new synthetic progestagen, Org 2969 (13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol) and its presumed active metabolite, 3-keto-Org 2969, were studied in five healthy female volunteers. During the first part of the study (Phase I), four volunteers ingested as a single dose 50 µg (about 100 µCi) of [16-³H]-Org 2969 together with 50 µg of ethinyl oestradiol. During the second part (Phase II), ten days of pretreatment with non-readioactive Org 2969 and ethinyl oestradiol preceded dosing, which was similar to that in Phase I. The fifth volunteer ingested 2500 µg of Org 2969 as a single dose. The concentrations of Org 2969 and 3-keto-Org 2969 in serum were measured by specific radioimmunoassay, and by as radioactivity. The maximum serum level of Org 2969 of 0.2–0.3% of the dose/litre was obtained 0.8–1.3 h after administration, and it was followed by a mono-exponential decrease, the half-life being 1.3–1.5 hours. No difference in Org 2969 levels was seen between Phase I and Phase II studies. The maximum 3-keto-Org 2969 serum level in Phase I was 0.4–0.8% of the dose/litre, 1–3 h after administration. A two-compartment open body model adequately described the data. The half-life of elimination was 16 hours. There was a considerable change in the single dose kinetics between Phase I and Phase II in the case of 3-keto-Org 2969. In Phase II the maximum serum level was 2.0–3.4% of the dose/litre, and there was no significant change in half-life. The change was considered to be due to a decrease in the apparent volume of distribution as a result of an increased number of binding sites on sex hormone-binding globulin induced by ethinyl oestradiol during the pretreatment period, and/or to an increase in the fraction of Org 2969 metabolized to 3-keto-Org 2969. The two simultaneous processes contributed to the change in kinetics and to the production of a steady state level of 3-keto-Org 2969 which resulted in a steady state within the first 10 days of daily administration of Org 2969 and ethinyl oestradiol.