SULFAMATES OF VARIOUS ESTROGENS ARE PRODRUGS WITH INCREASED SYSTEMIC AND REDUCED HEPATIC ESTROGENICITY AT ORAL APPLICATION

Oral therapy with natural or synthetic estrogens, like ethinylestradio l, suffers from low, suboptimally defined bioavailability and excess h epatic estrogen actions. N,N-alkylated and non-alkylated sulfamates of ethinylestradiol, estradiol and estrone overcome these deficiencies. Ovariectomized Wistar rats (n = 6-7/group) were orally treated for 7 d ays, and killed on day 8, plasma was gained on days 0, 4, and 8. Syste mic estrogenicity was quantified by assessment of uterine weight, vagi nal cornification, and measurement of gonadotropins by homologous RIA. Estrogenicity in the liver was analysed. Angiotensinogen was estimate d by RIA of angiotensin-l after incubation of EDTA-plasma with porcine renin. Total and high-density cholesterol were measured by enzymatic methods. Preliminary biotransformation studies were performed after or al administration of 10 mu g, 5 mu Ci [2,4,6,7-H-3] estradiol sulfamat e. Ethinylestradiol led to distinct elevation of angiotensin-l and dra matic depression of cholesterol fractions, reflecting hepatic estrogen effects, already at doses with marginal systemic effects. Estradiol a nd estrone had systemic and hepatic estrogenic activity at much higher doses only. Estrogen sulfamates had systemic estrogen activity 10-90- fold above that of their parent estrogen. Non-alkylated sulfamates of given estrogens were more active than N-alkylated ones. Elevation of s ystemic estrogen activity was always combined with a dramatic reductio n of hepatic estrogenicity. Estradiol sulfamate had a 90-fold elevated systemic estrogen activity vs estradiol, but lacked hepatic activity including the 30-fold dose inducing vaginal response. Three hours afte r administration no unchanged estradiol sulfamate was detectable in pl asma. Rather peaks, probably representing estradiol and estrone, were found. Estrogen sulfamates are considered prodrugs of their parent est rogen, which do not interact with any liver function during the first- pass. They represent a new strategy of oral hormone administration. Th eir main potential seems to be the systemic generation of natural estr ogens when used in oral contraceptives.