Pharmacokinetics of ethynyloestradiol in women for different populations.

The pharmacokinetics of a dose of 50 microgram ethynyloestradiol administered orally was studied in fourteen centres. Absorption was rapid and the highest serum concentrations of total ethynyloestradiol were found in most subjects at 1 h and by 24 h concentrations were less than 250 pg/ml. Calculation of the half-lives for absorption, distribution and elimination showed wide variations between subjects, the half-life of elimination varying from 2.5 h to more than 30 h. Bioavailability as measured by the area under the serum ethynyloestradiol concentration-time curve also showed more than a ten-fold variation. Intra-centre differences in the various parameters measured were as large as the inter-centre differences.

Assay of ethynyloestradiol in human serum and its binding to plasma proteins.

PIP: A radioimmunoassay for estimating both unconjugated and conjugated ethinyl estradiol (EE) in serum is described, along with a report of levels of EE attained after its administration and the binding of EE in plasma, as determined by this radioimmunoassay. Mean values for concentration of free EE were 38-87 pg/ml, 1-4 hours after administration, and by 24 hours levels in most subjects were below the sensitivity level of this assay, which is less than 25 pg/ml. Conjugated EE concentration in serum was considerably higher, with mean values of 370-770 pg/ml 1-4 hours after ingestion, decreasing slowly to mean values of 285 pg/ml at 8 hours and 100 pg/ml at 24 hours postadministration. Total EE (conjugated plus unconjugated) had a mean half-life of 3.8 hours during the period 2-8 hours after administration and 10.7 hours for the period 8-24 hours postadministration. EE in plasma was shown, by equilibrium dialysis, gel filtration on Sephadex G200, and polyacrylamide gel electrophoresis, to bind only to albumin, and no specific binding of EE occurred. The apparent association constant for the binding of EE to human serum albumin was 1.7 times 10 5 liter per mol.^ieng

Bioavailability of Lynestrenol.

The bioavailability of lynestrenol and ethynyloestradiol from a capsule formulation was superior to a normal tablet formulation. Bioavailability, as measured by the area under the plasma concentration curves, showed, particularly in the case of the capsule formulation, that all of the administered lynestrenol was converted to norethisterone.

PIP: An in vivo research study demonstrated that the bioavailability of lynestrenol and ethynyloestradiol administrered in capsule form was equal to or slightly greater than when it was administered in normal tablet form. Lynestrenol was metabolized to norethisterone both in vivo and in vitro in previous investigations. 11 normal males were administer either 1 capsule containing 2.5 mg lynestrenol and 0.05 mg ethynyloestradiol or tablets containing the same dose of steroids. Blood samples were taken just before and 1,2,4,8, and 24 hours after the drugs were administered. 8 days later the subjects were given the opposite formulations and blood samples were again obtained at the same time intervals. Radioimmunoassay was used to assess levels of free and conjugated ethynyloestradiol and norethisterone in the serum samples. Biovailability assessments were made by calculating the areas under the time-concentration curves. Results demonstrated that the conversion of lynestrenol to norethisterone in vivo was complete. Unconjugated ethynyloestradiol mean values, 2 and 4 hours after administration of the drugs, were higher for capsules than for tablets. For blood samples taken at other time periods the mean values of unconjugated ethynyloestradiol were similar for both capsules and tablets. For conjugated ethynyloestradiol the mean values and the areas under the curve, for blood samples obtained at each time interval, showed no significant difference for tablets and capsules.

Binding of the contraceptive steroids medroxyprogesterone acetate and ethynyloestradiol in blood of various species.

PIP: This study compares the binding of medroxyprogesterone acetate (MPA) and 17a-ethynyloestradiol to plasma proteins of various species (baboons, monkeys, dogs, rabbits, guinea-pigs, rats) with that in man. Plasma samples were collected from each species and subjected to centrifugation, filtration; equilibrium dialysis and polyacrylamide gel electrophoresis (PAGE). The results confirm the presence in the plasma of the species examined of a protein with a high capacity and low affinity for ethynyl estradiol and MPA. This protein appears to be the albumin. Ethynyl estradiol was bound to a greater extent than MPA in each species. There was a lack of binding of ethynyl estradiol to SHBG (sex hormone binding globulin) in any species, nor was binding reduced by dihydrotestosterone. This was attributed to a general steric effect of the introduction of the 17-alpha ethynyl group. It was also shown that more than 90% of ethynyl estradiol is loosely bound, mainly to serum albumin, with similar apparent association constants; in all species except dog and guinea-pig, binding occurred only to albumin. For MPA, less binding of MPA than ethinyl estradiol occurred in all species except the rabbit, and binding was significantly lower in the guinea-pig than in the other species. PAGE showed that binding occurred only to albumin. Stability of MPA-albumin complexes on PAGE varied and appeared to be less stable than the ethynyl estradiol-albumin complex. These variations in stability may account for the differences in biological activities of the steroids in different species.^ieng

Measurement of ethynyloestradiol by radioimmunoassay and by isotope dilution-mass spectrometry.

PIP: A search of the literature reveals a wide discrepancy in measurements of plasma ethinyl estradiol in women using oral contraceptives (OCs) containing ethinyl estradiol. This would suggest that some of the measurement methods used may be unreliable and that validation of radioimmunoassay results by independent measurement methods is necessary. Serum samples were obtained from 27 women at varying times (from 2-24 hours) following oral administration of 50 mcg ethinyl estradiol. Measurement was made of total (free plus conjugated) ethinyl estradiol by radioimmunoassay and also by an isotope dilution-mass spectrometry (ID-MS) procedure. A scattergram presents the comparative results. The correlation between the 2 measurement methods was highly significant, p.001. The findings suggest that radioimmunoassay provides specific and accurate enough measurement of total ethinyl estradiol in blood. The findings cannot be extrapolated to measurement of free ethinyl estradiol. The fact that 1 method did not consistently give higher values than the other suggests that interference in the measurement from metabolites of the administered estrogen or from endogenously secreted estrogens is insignificant.^ieng