PHARMACOKINETICS OF LEVONORGESTREL AND ETHINYLESTRADIOL IN 9 WOMEN WHO RECEIVED A LOW-DOSE ORAL-CONTRACEPTIVE OVER A TREATMENT PERIOD OF 3 MONTHS AND, AFTER A WASH-OUT PHASE, A SINGLE ORAL-ADMINISTRATION OF THE SAME CONTRACEPTIVE FORMULATION

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 9 healthy women (age 23 to 42 years), during a treatment period of three months with a low-dose oral contraceptive; containing 0.15 mg LNG together with 0.03 mg EE2 (Microgynon(R)). After a wash-out period of 3 months, 8 of these women received a single administration of the same formulation. The results showed that there was an increase in serum trough levels of LNG, reaching steady-state in the second half of each treatment cycle. The LNG levels achieved were about 3 to 4 times higher than anticipated on the basis of single dose administration. At the end of treatment cycles one and three, the terminal half-life of LNG was in the range of 24-26 h, while a mean value of 20 h was observed following single dose administration. An EE2-induced increase in the SHBG concentration of about 50 % as compared to pretreatment values was observed during a treatment cycle. Pretreatment values were reached following the drug-free interval of 7 days between two cycles. After single dose administration, the free fraction of LNG was 1.3 +/- 0.2 % and the fractions bound to SHBG and albumin were 64.1 +/- 4.2 % and 34.6 +/- 4.0 %, respectively. Serum protein binding of LNG did not change during chronic treatment. An about 50 % reduction in total and unbound clearance of LNG was observed during chronic treatment, as compared to single dose administration. Increased SHBG binding capacity and a reduced hepatic metabolic capacity were discussed as possible causes of accumulating LNG concentrations in the serum. On the last day of treatment cycles one and three, the AUC(0-24h) values of EE2 were 728 +/- 314 and 778 +/- 318 pgx ml-1 x h, respectively, and were in keeping with data reported from others.