The pharmacokinetics of cyproterone acetate (CPA) and ethinylestradiol (EE2) were determined in 15 healthy women (age 19 to 34 years), following single dose administration of a combination oral contraceptive, containing 2.0 mg CPA together with 0.035 mg EE2 (Diane-35R). After a wash-out period of one week, the same preparation was administered during a treatment period of three months. After single dose administration, maximum concentrations of CPA in the serum were 15.2 +/- 6.6 ng/ml. Post maximum drug levels declined biphasically with half-lives of 0.8 +/- 0.4 h and 54.0 +/- 26.0 h, respectively. The apparent clearance was calculated to be 3.6 +/- 0.9 ml x min-1 x kg-1 and the volume of distribution (Vz) was 986 +/- 4371. The free fraction of CPA was 3.5 +/- 1.9% and the fractions bound to heat labile proteins and albumin were 4.6 +/- 2.2% and 92.0 +/- 3.5%, respectively. Trough levels of CPA in the serum increased during a treatment cycle, reaching a steady-state around day 16. An about two-fold accumulation of CPA was observed, which was less than expected theoretically. SHBG concentrations in the serum increased by a factor of three during a cycle, without having any effect on the protein binding of CPA. At the end of treatment cycle three, the terminal half-life of CPA had increased to a mean value of 78.6 +/- 16.0 h and the volume of distribution to a value of 1304 +/- 427 1. The apparent clearance showed a small, although significant decrease to a value of 3.0 +/- 0.4 ml x min-1 x kg-1. The observed changes Vz and t 1/2 during the treatment period were attributed to the distribution of CPA into a deep compartment and the slow release of the drug from this compartment. The AUC(0-4h) values of EE2 following single dose administration of the combination oral contraceptive were found to be 187.5 +/- 79.7 pg x ml-1 x h. On the last day of cycles one and three, the AUC(0-4h) values were 311.2 +/- 109.3 and 304.8 +/- 121.5 pg x ml-1 x h, respectively, which corresponds to an about 60% increase as compared to single dose administration. Total and free testosterone concentrations decreased during treatment cycles one and three by about 39% and 62%, respectively, compared with the corresponding values measured prior to treatment.
PIP: In Germany, 15 healthy young women received a single dose of an oral contraceptive (OC) (Diane-35R) with 2 mg cyproterone acetate (CPA) and .035 mg ethinyl estradiol (EE2) and, after a 2 week wash-out period, they received the same OC over a treatment period of 3 cycles. A drug-free interval separated each of the 3 cycles. The researchers aimed to examine the pharmacokinetics of CPA and EE2 of this OC. After 1 oral dose, CPA was rapidly absorbed and CPA serum levels rose as high as 15.2 ng/ml. 24 hours after the single dose, the free fraction of serum CPA was 3.5%. The fractions bound to albumin and heat labile proteins were 92% and 4.6%, respectively. The terminal half-life of CPA was higher at the end of treatment cycle 3 than after a single dose (78.6 hours vs. 54 hours). The apparent mean volume of distribution also increased from 986 to 1304. The apparent total clearance fell somewhat from 3.6 to 3 ml x min-1 x kg-1. Mean serum CPA trough levels rose during treatment and stabilized on day 16 of cycles 1 and 3. Accumulated CPA in the serum during treatment cycle 1 was more than 2 times higher than that expected based on data obtained after single dose administration. Serum concentration of sex hormone binding globulin increased by a factor of 3.3 during a treatment cycle due to concomitant administration of EE2. This increase did not affect the protein binding capacity of CPA. Distribution of CPA into a deep compartment (e.g., fatty tissue and skin) and the slow release of CPA from this compartment accounted for the increases in volume of distribution and the terminal half-life. The area under the curve of EE2 was about 60% higher on the last days of cycles 1 and 3 than it was after single dose administration (311.2 and 304.8, respectively vs. 187.5). When compared to baseline values, free and total testosterone levels fell during treatment cycles 1 and 3 by around 62% and 39%, respectively.