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). 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 pg x ml-1 x h, respectively, and were in keeping with data reported from others.
PIP: Scientists at Schering AG Research Laboratories in Berlin, Germany, analyzed the pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE2) in 23 to 42 year old women to study the effect of protein binding on the accumulation of LNG in the serum and to examine whether the clearance of free LNG changed during longterm use (3 treatment cycles) of a monophasic oral contraceptive (OC) with 0.15 mg LNG and 0.03 mg EE2. Blood samples were taken regularly to measure sex hormone binding globulin (SHBG) and LNG levels. During the 3-month treatment cycle, serum LNG trough levels rose until day 18, when they stabilized. LNG levels after a single dose of the OC were between 3 and 4 times greater than researchers expected. This higher dose may have been due to either EE2 or LNG impairing the hepatic metabolic capacity or there was an increase in serum SHBG binding capacity. The mean terminal half life of LNG after a single dose stood at 20 hours, whereas it was between 24 to 26 hours at the end of treatment cycles 1 and 3. EE2 increased the SHBG level around 50%. The free LNG fraction after 1 dose stood at 1.3%, while the LNG fraction bound to SHBG and to albumin stood at 64.1% and 34.6%, respectively. Longterm use did not affect serum protein binding of LNG. Between single dose and longterm administration, the total and unbound clearance of LNG fell around 50%. The area under the curve values of EE2 and 728 pg x ml-1 x hour at 0 hours and 778 pg x ml-1 x hour at 24 hour, which corresponded with data from other studies. These results indicated that the steady serum levels of LNG depend on the dose of LNG and are associated with the fall in total clearance, which in turn appear to be a mixture of changes in intrinsic clearance and changes in protein binding of LNG.