PHARMACOKINETICS OF LEVONORGESTREL AND ETHINYLESTRADIOL IN 14 WOMEN DURING 3 MONTHS OF TREATMENT WITH A TRI-STEP COMBINATION ORAL-CONTRACEPTIVE - SERUM-PROTEIN BINDING OF LEVONORGESTREL AND INFLUENCE OF TREATMENT ON FREE AND TOTAL TESTOSTERONE LEVELS IN THE SERUM

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE( 2)) were determined in 14 healthy women (age 18 to 27 years) during a treatment period of three months with a tri-step combination oral cont raceptive (TriquilarR). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.125 mg LNG together with 0.03 mg EE(2). There was a washout phase of one w eek between both treatments. Following single dose administration, a m ean terminal half-life of 22 h was observed for LNG. The total clearan ce was 1.0 ml x min(-1) x kg(-1) and the volume of distribution was 12 8 l. During a treatment cycle, LNG levels in the serum accumulated by a factor of about four as compared to single dose administration. Stea dy-state drug levels were reached during the second half of each cycle . As compared to single dose administration, the following changes wer e observed for LNG at the end of treatment cycles one and three: reduc ed total (0.5 ml x min(-1) x kg(-1)) and free clearance (50 ml x min(- 1) x kg(-1)) and a reduced volume of distribution (52 l). A concomitan t increase in the SHBG concentrations by a factor of two as compared t o pretreatment values tvas observed during treatment and appeared to b e mainly responsible for the changes in the pharmacokinetics of LNG. M arked changes were also seen for the serum protein binding of LNG. Aft er single dose administration, the free fraction of LNG was 1.4 % and the fractions bound to SHBG and albumin were 55.0% and 43.6%, respecti vely. At the end of cycle one, the free fraction was only 1.0% and the fractions bound to SHBG and albumin were 69.4% and 30.0%, respectivel y. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of LNG at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h ) values of EE(2) were 331.2 and 369.6 pg x ml(-1) x h, respectively, which corresponds to an about 11-24% increase as compared to single do se administration, where an AUC(0-4h) value of 298.3 pg x ml(-1) x h w as found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 41% and 55%, respectively, com pared with the corresponding values measured prior to treatment.