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  • Title: Pharmacokinetics of gestodene and ethinylestradiol in 14 women during three months of treatment with a new tri-step combination oral contraceptive: serum protein binding of gestodene and influence of treatment on free and total testosterone levels in the serum.
    Author: Kuhnz W, Baumann A, Staks T, Dibbelt L, Knuppen R, Jütting G.
    Journal: Contraception; 1993 Oct; 48(4):303-22. PubMed ID: 8222659.
    Abstract:
    The pharmacokinetics of gestodene (GEST) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 32 years) during a treatment period of three months with a new tri-step combination oral contraceptive (Milvane). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.1 mg GEST together with 0.03 mg EE2. There was a wash-out phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 18 h was observed for GEST. The total clearance was 0.9 ml x min-1 x kg-1 and the volume of distribution was 84 l. During a treatment cycle, GEST levels in the serum accumulated by a factor of 8 as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for GEST at the end of treatment cycles one and three: prolonged terminal half-life (20 to 22 h), reduced total (0.16 ml x min-1 x kg-1) and free clearance (ca. 27 ml x min-1 x kg-1), reduced volume of distribution (ca. 18 l). A concomitant EE2-induced increase in the SHBG concentrations by a factor of three as compared to pretreatment values was observed during a treatment cycle and appeared to be mainly responsible for the changes in the pharmacokinetics of GEST. Marked changes were also seen for the serum protein binding of GEST. After single dose administration, the free fraction of GEST was 1.3% and the fractions bound to SHBG and albumin were 69.4% and 29.3%, respectively. At the end of cycle one, the free fraction was only 0.6% and the fractions bound to SHBG and albumin were 81.4% and 18.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of GEST at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 299.2 and 278.1 pg x ml-1 x h, respectively, which corresponds to an about 30% increase as compared to single dose administration, where an AUC(0-4h) value of 216.1 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 36% and 60%, respectively, compared with the corresponding values measured prior to treatment. The fraction of unbound testosterone thus decreased from 0.5% to 0.3% during treatment. In Germany, researchers examined blood samples from 14 healthy young women, who first took a single oral dose of 0.1 mg gestodene and .03 mg ethinyl estradiol, then Milvane, a new tri-step combination oral contraceptive, for 3 months, to learn in detail the pharmacokinetics of gestodene. A 1-week wash-out phase occurred between the 2 treatments. The mean terminal half-life for gestodene after receiving the single dose was 18 hours. It volume of distribution stood at 84. Total clearance was 0.9 ml x min-1 x kg-1. Gestodene serum levels accumulated by a factor of 8 when compared to levels after single-dose administration. Drug levels reached a steady-state by the second part of each treatment cycle. At the end of treatment cycles 1 and 3, in comparison with single-dose administration, gestodene had a prolonged terminal half-life (20-22 h), reduced total and free clearance (0.16 ml x min-1 x kg-1 and ca. 27 ml x min-1 x kg-1, respectively), and reduced volume of distribution (ca. 18 1). When comparing single-dose administration and 3-month treatment levels, ethinyl estradiol increased sex hormone binding globulin (SHBG) levels by a factor of 3, apparently causing the changes in the pharmacokinetics of gestodene. Further, the free fraction of gestodene fell from 1.3 to 6%, and the fractions bound to SHBG increased from 69.4 to 81.4% while the fractions bound to albumin fell from 29.3 to 18%. The ethinyl estradiol values of the area under the curve stood at 299.2 pg x ml-1 x h at 0 hours of the last day of treatment cycle 1 and 3. At 4 hours, it was 278.1 pg x ml-1 s h. Between pretreatment and treatment cycles 1 and 3, total and free testosterone levels fell by almost 36% and 60%, respectively, resulting in a decrease of the fraction of unbound testosterone from 0.5 to .03% during treatment. These findings showed that pharmacokinetic parameters did not differ between cycles 1 and 3, indicating that equilibrium had been already reached after one cycle and that prolonged treatment should not result in any other changes.
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