Single and multiple administration of a new triphasic oral contraceptive to women: pharmacokinetics of ethinyl estradiol and free and total testosterone levels in serum.

Ethinyl estradiol is part of almost every combined oral contraceptive, and its pharmacokinetic characteristics have been thoroughly investigated in numerous studies. However, little is known about its pharmacokinetics during long-term administration, as compared with single-dose administration. In this study 10 women received a triphasic formulation that contained ethinyl estradiol together with the progestin gestodene over one treatment cycle. Mean area under the curve values of ethinyl estradiol were significantly higher on the last treatment day, as compared with the corresponding values obtained from the same women after single-dose administration. However, the observed increase in area under the curve was within the range of pharmacokinetic accumulation, to be expected on the basis of dosing interval and terminal half-life. Another point of interest was the effect of the triphasic preparation on testosterone concentrations in serum. Both total and free testosterone levels were suppressed by about 60% as compared with pretreatment values, and there was no correlation with corresponding sex hormone-binding globulin levels in the serum.

PIP: Researchers at the research laboratories of Schering, AG pharmaceutical company in Berlin, Germany compared basic pharmacokinetic parameters of ethinyl estradiol and free and total testosterone in 10 women after single dose administration of a triphasic oral contraceptive (OC) containing .1 mg gestodene and .03 mg ethinyl estradiol with the corresponding parameters from a complete treatment cycle (.01-.05 mg gestodene and .03-.04 mg ethinyl estradiol). A 220% increase in serum sex hormone binding globulin concentration occurred over 1 treatment cycle. Total and free testosterone concentrations fell equally. Indeed they fell about 60% on day 21 compared to the values on day 21 of the pretreatment cycle. Therefore the triphasic OC caused a drop in testosterone production. No association existed between total and free testosterone concentrations and corresponding sex hormones binding globulin levels. A 38-48% significant increase in the area under the curve levels of serum ethinyl estradiol occurred on day 21 during long term treatment with the triphasic OC compared to during single dose administration. The researchers posed several explanations for this increase. For example, an irreversible interaction of ethinyl estradiol with cytochrome P-450 enzymes may have impaired the hepatic metabolic capacity. Further studies are needed to determine conclusively why ethinyl estradiol levels increased.

Studies on the biotransformation of lonazolac, bromerguride, lisuride and terguride in laboratory animals and their hepatocytes.

1. Metabolic patterns and the extents of metabolism of four drugs, namely [14C]lonazolac (LON), [14C]bromerguride)BRO), [14C]lisuride (LIS) and [3H]terguride (TER) have been studied in three experimental models, namely hepatocyte suspensions of rat, guinea pig, beagle dog and cynomolgus monkey, isolated perfused liver of rat and guinea pig and intact animals (rat, guinea pig, dog and monkey). 2. Selection of compounds was based on differences in phase I metabolic pathways. LON is exclusively hydroxylated in the N-substituting aromatic ring, BRO is mainly N-deethylated in the urea moiety, and LIS and TER are both degraded into numerous metabolites. 3. The decrease in unchanged drug levels in hepatocyte suspensions was characterized by half-lives, with LON as the most stable and LIS as the least stable compound. Marked interspecies differences were found. De-ethylation and aromatic hydroxylation were much slower in rat hepatocytes than in the liver cells of other species; BRO was slowly biodegraded in dog hepatocytes while LIS was broken down extremely quickly. 4. Liver perfusion experiments and studies in vivo were evaluated for the extents of metabolism of each drug. 5. Metabolism studies in hepatocytes did not show any quantitative correlation to those of metabolism in vivo. The suitability of evaluating parameters for in vitro studies is discussed.