Tazewell S. Dozier

Plasma levels and pharmacokinetics of ethynyl estrogens in various populations

A study to determine the pharmacokinetics of single doses of ethynylestradiol (EE) of 35-100 ug administered to a total of 98 women in the United States, Thailand, Nigeria, Sri Lanka, and Singapore. After EE ingestion, plasma samples were collected at various intervals with 65% of U.S. patients exhibiting peak plasma EE levels between 60-90 minutes, and 2/3 showed detectable EE levels at 24 hours using 50-80 ug doses. To assess within-subject variation and range of variation between individuals, subjects in Palo Alto using 35 ug doses were tested twice showing a variation within subjects of 51.8% and between subjects was 119%. In Tucson, subjects using 100 ug EE doses showed a within-subject variation of 13.5% and between subjects was 37%. Absorption phase half-life ranged from 14-22 minutes, distribution phase varied from 1-3 hours, and the elimination half life ranged from 6-14 hours. Nigeria indicated the lowest plasma EE levels while Thailand had the highest levels even when body surface differences were accounted for. Dietary differences may cause differences in drug absorption; in addition, differences in relative muscle/fat ratios could effect storage and metabolism.

Comparative studies of the Ethynyl Estrogens used in Oral Contraceptives. VII. Effects with and without Progestational Agents on Ultracentrifugally Fractionated Plasma Lipoproteins in Humans, Baboons, and Beagles *

Ethynyestradiol and mestranol, in doses ranging from 50 to 100μg/day, were given to women in 21-day cycles; baboons and beagle dogs received 1 and 4μg/kg/day in a similar regimen. After a number of such cycles, megestrol acetate, norethindrone acetate, or dl-norgestrel was given concomitantly. Protein, cholesterol, triglyceride, and phospholipid levels were determined in total plasma and in ultracentrifugally separated lipoprotein fractions. Over the dosage range studied, the effects of the two kinds of estrogen were indistinguishable. Except for human total plasma triglyceride, no dose-related differences were observed. The lowering of serum protein and the increase in cholesterol induced by estrogen were more pronounced in baboons and beagles than in human subjects. The cholesterol-depressing effect of progestational compounds observed in humans was very pronounced in baboons but absent in beagles. In all three species, estrogen increased the lipoprotein fraction cholesterol, except for human low-density lipoprotein cholesterol, which was decreased. Human plasma triglyceride and phospholipid increased on estrogen administration and were decreased by the progestins; in the two animal species, triglyceride is normally very low and the estrogen-induced changes were negligible; the phospholipid rose with estrogen but was unaffected by progestins. In sum, the two animal species show many similarities to, as well as important differences from, the human response of plasma lipids to various contraceptive steroids.

Plasma levels and pharmacokinetics of ethynyl estrogens in various populations: II. Mestranol☆

Abstract A total of 89 adult women from Nigeria, Singapore, Sri Lanka, Thailand and the USA were given single oral doses of mestranol ranging from 50 to 100 μg; the subsequent plasma levels of free mestranol and ethynylestradiol were determined by radioimmunoassay, and certain pharmacokinetic parameters calculated. Mestranol is absorbed very rapidly from the digestive tract and maximum plasma levels are attained in 1–4 hours, the majority at 1–2 hours. Detectable levels of mestranol are present 24 hours postingestion in 58% of subjects after a 50 μg dose and in 79% after a 100 μg dose. At all dose levels, highest plasma mestranol levels and area under the curve of plasma levels (AUC) occurred in Sri Lankan women, and lowest plasma levels in Nigerian women, even when corrected for body surface differences. Plasma levels of ethynylestradiol derived from mestranol rose earlier and reached higher values than those of mestranol itself in every locality. The plasma levels of ethynylestradiol derived from mestranol were lowest and total body clearance highest in the Nigerian group at all dose levels; total body clearance was similar in the other localities. The AUC of plasma levels of ethynylestradiol was compared, by locality, on a dose-for-dose basis for the administration of mestranol or of ethynylestradiol itself. There was no significant difference between the two drugs, except at one dosage level in Thailand. These findings suggest that ethynylestradiol and mestranol are similar in terms of AUC ; a higher peak and a faster decline are observed after administration of the former compound. Substantial differences between localities in the clearance rates of mestranol are suggested; whether these are due to differences in distribution or rate of metabolism or to differences in absorption remains to be determined.

Diagnosis of early pregnancy in the baboon.

The reliability and rapidity of methods utilizing radioimmunoassay ( RIA) for detecting chorionic gonadotropin (CG) and estrogens in plasma, competitive protein binding assay for plasma progestins, and the hemagglutination inhibition test for urinary CG in the diagnosis of early pregnancy was evaluated in baboons. The hemagglutination inhibition test for detection of urinary CG did not give satisfactory results as late as Day 25 of pregnancy. Confirmation of pregnancy could not be established on Days 8 and 12 of pregnancy by RIA of estrogens, progestins, or CG. However, detection of plasma CG by RIA was 96.6% successful by Day 16, though the method was time-consuming. However, the determination of plasma estrogens and progestins by RIA was determined more quickly on Day 16, and gave equally successful results as the RIA for CG.

Comparative Studies of the Ethynyl Estrogens used in Oral Contraceptives. VI. Effects with and without Progestational Agents on Carbohydrate Metabolism in Humans, Baboons, and Beagles *

Human subjects, baboons, and beagles were given cyclic regimens of ethynylestradiol or mestranol; after a number of such cycles, concurrent administration of norethindrone acetate, dl-norgestrel, or megestrol acetate was introduced for a similar number of cycles. Carbohydrate tolerance was evaluated by oral glucose tolerance testing in the human subjects and by intravenous glucose tolerance testing in the baboons and beagles. In the human subjects, neither mestranol nor ethynylestradiol at daily doses of 50 to 100 microgram/day produced any effect on fasting glucose levels or on glucose tolerance even after six cycles of treatment. The addition of the progestational compounds also had no effect on these two variables. In baboons, ethynylestradiol and mestranol were bioequivalent and produced a dose-related decrease in the glucose disposal rate. All three progestational agents counteracted this effect in a comparable manner. In beagles, on the other hand, estrogens produced an increase in the glucose disposal rate, and the addition of progestational agents produced an initial fall and a subsequent return to pretreatment levels.

Comparative studies of the ethynyl estrogens used in oral contraceptives: effects with and without progestational agents on plasma androstenedione testosterone and testosterone binding in humans baboons and beagles.

The effects of ethynylestradiol or mestranol given in cyclic fashion, with and without a progestational compound (norethindrone acetate, dl-norgestrel, or megestrol acetate), on plasma androgens and their binding were examined in adult women, female baboons, and beagles. The two estrogens are equivalent in their effect, and there were essentially no dose-related differences over the range examined. In human subjects, the estrogens increased total testosterone and testosterone binding, and decreased free testosterone. In baboons, estrogen produced a transient decrease in total testosterone and an increase in binding. The levels of progestational agents used did not affect total testosterone in humans, as is commonly observed with commercial agents, but did decrease it in baboons. Percentage binding was decreased in both species by the 19-nor compounds, but not by megestrol. Androstenedione levels were unaffected in human subjects, but effects of both estrogens and progestins were seen in baboons. Because of the very low levels of androgens in female beagles, this species did not lend itself well to a study of this kind. However, an increase in testosterone binding was induced by estrogen even in the absence of testosterone/estrogen-binding globulin.

Comparative Studies of the Ethynyl Estrogens Used in Oral Contraceptives: Effects with and without Progestational Agents on Plasma Cortisol and Cortisol Binding in Humans, Baboons, and Beagles *

Ethynylestradiol and mestranol, in doses ranging from 50 to 100μg/day, were given to women in 21-day cycles; baboons and beagle dogs received 1 and 4μg/kg/day in a similar regimen. After a number of such cycles, megestrol acetate, norethindrone acetate, or dl-norgestrel was given concomitantly. Plasma cortisol and percentage binding of cortisol were determined, and the level of free cortisol was calculated. Over this dosage range the effect of the two kinds of estrogen was indistinguishable. In women, 100μg/day produced slightly higher levels of total plasma cortisol than 50μg/day, but no other dose-related differences were seen in any of the three species. Estrogen caused a rise in total cortisol (implying an increased synthesis of transcortin by the liver) in humans and baboons; in the beagle, total cortisol fell transiently. In all three species, the percentage binding of cortisol increased during estrogen administration. There was a very slight, statistically demonstrable increase in total and free cortisol levels in humans and baboon, none in dogs. Of the three progestational compounds, norethindrone acetate and norgestrel produced a slight decrease in total cortisol, whereas megestrol had no effect in humans. The free cortisol was unaltered by these compounds. In both the baboon and the dog, the response was complex, and different from that seen in human subjects. The dog appears to be an inappropriate surrogate for man in the study of these hormonal effects. The validity of the baboon with respect to this progestin-induced effect requires further study; however, its response to estrogens is similar to that of man.