Comparative pharmacokinetics of two new steroidal estrogens and ethinylestradiol in postmenopausal women

It was the aim of the study to compare the pharmacokinetic properties of the two new estrogens, ZK 136295 and ZK 115194, with those of ethinylestradiol (EE(2)) after single intravenous (60 mu g) and oral (120 and 240 mu g) administration in 54 postmenopausal women. In particular, our objective was to examine whether one or both compounds were characterized by an improved oral bioavailability with less inter-subject variability than EE(2). Drug serum concentrations were determined using specific radioimmunoassays for EE(2) and ZK 136295, and a GC/MS/MS-method for ZK 115194. Following iv administration of the new estrogens and of EE(2), the drugs were rapidly distributed in the body. The mean terminal half-lives were calculated to be 12.3 +/- 12.4, 28.7 +/- 9.6, and 26.1 +/- 11.1 h for ZK 136295, ZK 115194, and EE(2), respectively. After oral administration of 120 mu g, the absolute bioavailability was calculated to be about 40% for ZK 136295 as well as for EE(2) with a high inter-individual variation (variation coefficient: 44 and 67%). By doubling the dose, the systemic availability increased dose-dependently for both drugs to about 70% with the same high interindividual variation. Following single oral administration of 240 mu g ZK 115194, the absolute bioavailability amounted to 33 +/- 19%. The present study clearly revealed that although the two new estrogens differed considerably in their pharmacokinetic behavior, they demonstrated a reduced and highly variable systemic availability similar to that of EE(2). (C) 1996 Elsevier Science Inc.