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17 alpha-Ethynylestradiol (EE2)[20,21-14C] and [9,11-3H] were administered by intragastric intubation to three adult female rhesus monkeys. Quantification of the tritium isotope indicated that the peak plasma radioactivity (3.4-6.8% of dose) occurred between 30 and 60 min, whereas 36-39% of the administered tritium appeared in the urine in the first 96 hr. Fecal excretion was 9.17.0% during the same period. Fractionation and isolation of the urinary conjugates were accomplished by chromatography on Sephadex LH-20 followed by HPLC. Cochromatography of radioactive fractions with authentic steroid glucuronide standards gave presumptive evidence for the presence of ethynylestradiol and estrone glucuronides. Following hydrolysis, the tritium-labeled natural estrogens, estrone and estradiol-17 beta, were identified with reverse-isotope recrystallization, demonstrating that the de-ethynylation of EE2 had occurred.

The metabolism and elimination of estradiol (E2) and ethynylestradiol (EE2) were examined in adult female rhesus monkeys treated with two different combinational oral contraceptive agents at 10x the human equivalent dose. Ethynerone/mestranol (20:1), anagestone/mestranol (10:1), or vehicle was administered by gavage over a 10-year period on a cycling schedule of 21 days of dosing followed by 7 days without. At the end of the 28-day cycle, six monkeys in each group were anesthetized and administered a 14C-E2/3H-EE2 dose iv. Serial blood samples collected before and up to 6 hr after dosing were analyzed for total radioactivity and the percentage of parent compound and each metabolite was determined by HPLC. Radioimmunoassay of the baseline samples revealed that the plasma concentration of endogenous E2 was lower in the ethynerone/mestranol-treated group as compared to the vehicle control group. The total radioactivity derived from 14C-E2 was more rapidly eliminated from the plasma of the ethynerone/mestranol group than the control group. In addition, the percentages of HPLC-resolved E2 and EE2 were less in the treated group while the percentages of estrone, estrone glucuronide, and EE2 3-sulfate were enhanced as compared to the control group. The anagestone/mestranol group exhibited the same trends as the ethynerone/mestranol group but the data were not generally statistically different from the control group. These data indicate that chronically administered progestin/estrogen oral contraceptive agents reduce endogenous plasma E2 concentrations at least in part by enhancing the biotransformation of E2 to rapidly eliminated metabolites.