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Magnetic resonance was used to investigate the kinetic disposition of magnetite nanoparticles (9.4 nm core diameter) from the blood circulation after intravenous injection of magnetite-based dextran-coated magnetic fluid in female Swiss mice. In the first 60 min the time-decay of the nanoparticle concentration in the blood circulation follows the one-exponential (one-compartment) model with a half-life of (6.9 +/- 0.7) min. The X-band spectra show a broad single line at g approximately 2, typical of nanomagnetic particles suspended in a nonmagnetic matrix. The resonance field shifts toward higher values as the particle concentration reduces, following two distinct regimes. At the higher concentration regime (above 10(14) cm(-3)) the particle-particle interaction responds for the nonlinear behavior, while at the lower concentration regime (below 10(14) cm(-3)) the particle-particle interaction is ruled out and the system recovers the linearity due to the demagnetizing field effect alone.

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The pharmacokinetic parameters of estradiol (E2, CAS 50-28-2), free and total estrone (E1, CAS 53-16-7) were determined in 14 young women following a single oral administration of 2, 4 and 8 mg E2 and a single intravenous administration of 0.3 mg E2 in an open, intraindividual comparison with 4 treatments. The purpose of the study was to determine the absolute bioavailability of orally administered E2 in a larger group of women and to assess the inter- and intraindividual variability of basic pharmacokinetic parameters of E2 and metabolically derived E1. In addition, the outcome of this study should provide a basis for the decision whether E2 could potentially be used in a combination oral contraceptive. There was a dose proportional increase in the AUC-values following the oral administration of 2 mg and 4 mg doses of E2. At the high dose of 8 mg, however, only about 76%, 78% and 70% of the expected values were found for E2, free and total E1, respectively. Especially the reduction in total E1 concentrations points to an incomplete absorption of E2 at the high dose level. The absolute bioavailability of orally administered E2 was calculated based on the 4 mg dose and was found to be 4.9 +/- 5.0%. The mean ratio of free E1 and E2 concentrations in the serum, following parenteral and oral administration of E2 was about 1.0 (i.v.) and between 8.8 to 19.8 (p.o.), respectively. Pharmacokinetic parameters, like AUC, derived from serum level-time curves of E2, free and total E1 showed a high intra- and interindividual variability.(ABSTRACT TRUNCATED AT 250 WORDS)

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The pharmacokinetics of gestodene (GEST) was determined in 12 healthy women (age 22 to 34 years), following single dose administration of 0.075 mg GEST. The same preparation was also administered during one treatment cycle after a wash-out phase of 1 week. After single dose administration, maximum concentrations of GEST in the serum were 4.9 +/- 2.5 ng/ml. Post maximum drug levels declined biphasically with half-lives of 0.2 +/- 0.2 h and 14.9 +/- 6.7 h, respectively. The apparent clearance was calculated to be 0.8 +/- 0.4 ml x min-1 x kg-1. The free fraction of GEST was 1.3 +/- 0.3% and the fractions bound to SHBG and albumin were 64.3 +/- 10.7% and 34.4 +/- 10.4%, respectively. The results showed that there was a gradual decrease in serum trough levels of GEST during the cycle, due to a concomitant and equally high decrease in SHBG concentrations in the serum of about 26%. At the end of one treatment cycle, the free fraction of GEST increased to 1.8 +/- 0.5%, the SHBG-bound fraction decreased to 57.0 +/- 10.2% and the albumin-bound fraction increased to 41.3 +/- 9.9%. Total serum clearance increased during the same time period from a mean value of 0.8 to about 1.2 ml x min-1 x kg-1. The clearance of unbound GEST, however, remained unchanged. An examination of the free GEST concentrations revealed the same time course of GEST trough levels during the cycle as the simulated curve. This was derived from the pharmacokinetic parameters which were obtained after single dose administration. Thus, the present study showed that the pharmacokinetics of GEST can be fully explained on the basis of single dose pharmacokinetics and the changes in serum protein binding which were caused by a reduction of SHBG levels in the serum during chronic treatment with GEST. There was no evidence of GEST inhibiting its own metabolism.

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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.

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Two low-dose oral contraceptives, both containing the same dose of ethinyl estradiol (EE2) but different progestins (gestodene and desogestrel, respectively), were compared with respect to the relative bioavailability of EE2. After single-dose administration of both formulations to 18 women in an intraindividual cross-over design, there was no difference in the target variables for EE2 (Cmax, tmax and AUC). With respect to EE2, both formulations were bioequivalent. The observation of others, reporting higher EE2 levels in the serum of women taking the gestodene-containing formulation as compared to those taking the desogestrel-containing formulation, was not confirmed.

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