title: Estradiol prodrugs (EP) for efficient oral estrogen treatment and abolished effects on estrogen modulated liver functions.
abstract: Oral compared to parenteral estrogen administration is characterized by reduced systemic but prominent hepatic estrogenic effects on lipids, hemostatic factors, GH-/IGF I axis, angiotensinogen. In order to avoid such adverse metabolic effects of oral treatment, estradiol (E2) prodrugs (EP) were designed which bypass the liver tissue as inactive molecules. Carbone17-OH sulfonamide [-O2-NH2] substituted esters of E2 (EC508, others) were synthesized and tested for carbonic anhydrase II (CA-II) binding. CA II in erythrocytes is thought to oppose extraction of EP from portal vein blood during liver passage. Ovariectomized (OVX, day minus 14) rats were orally treated once daily from day 1-3. Sacrifice day 4. Uteri were dissected and weighed. Cholesterol fractions and angiotensinogen were determined in plasma. Oral E2 and ethinyl estradiol (EE) generated dose related uterine growth and important hepatic estrogenic effects. EP induced uterine growth at about hundred-fold lower doses. This was possible with almost absent effects on plasma cholesterol or angiotensinogen. Preliminary pharmacokinetic studies with EC508 used intravenous and oral administration in male rats. Resulting blood levels revealed complete oral bioavailability. Further high blood- but low plasma concentrations indicated erythrocyte binding of EC508 in vivo as potential mechanism of low extraction at liver passage. Very high systemic estrogenicity combined with markedly lower or absent adverse hepatic estrogenic effects is evidence for a systemic release of E2 from sulfonamide EP. In conclusion, tested oral EP bypass the liver in erythrocytes furnishing systemic estradiol at hydrolysis. This mechanism avoids the hepatic estrogenic impact of conventional oral estrogen therapy.
authors.affiliation: Evestra, Inc., 14805 Omicron Drive, Suite 100, San Antonio, TX 78245, USA.
authors.forename: W
authors.initials: W
authors.lastname: Elger
authors.affiliation: Innovent e.V., Prüssingstraße 27B, 07745 Jena, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Wyrwa
authors.affiliation: Evestra, Inc., 14805 Omicron Drive, Suite 100, San Antonio, TX 78245, USA.
authors.forename: G
authors.initials: G
authors.lastname: Ahmed
authors.affiliation: Evestra, Inc., 14805 Omicron Drive, Suite 100, San Antonio, TX 78245, USA.
authors.forename: F
authors.initials: F
authors.lastname: Meece
authors.affiliation: Evestra, Inc., 14805 Omicron Drive, Suite 100, San Antonio, TX 78245, USA.
authors.forename: H B
authors.initials: HB
authors.lastname: Nair
authors.affiliation: Evestra, Inc., 14805 Omicron Drive, Suite 100, San Antonio, TX 78245, USA.
authors.forename: B
authors.initials: B
authors.lastname: Santhamma
authors.affiliation: University of Arizona College of Medicine, 1501 N Campbell Ave, Tucson, AZ 85724, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Killeen
authors.affiliation: Evestra, Inc., 14805 Omicron Drive, Suite 100, San Antonio, TX 78245, USA.
authors.forename: B
authors.initials: B
authors.lastname: Schneider
authors.affiliation: Beuth University of Applied Science, Luxemburger Str. 10, 13353 Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Meister
authors.affiliation: Friedrich Schiller University Jena, Fürstengraben 1, 07743 Jena, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Schubert
authors.affiliation: Evestra, Inc., 14805 Omicron Drive, Suite 100, San Antonio, TX 78245, USA. Electronic address: knickisch@evestra.com.
authors.forename: K
authors.initials: K
authors.lastname: Nickisch
mesh_terms: D000284:Administration, Oral; D000808:Angiotensinogen / Q000097:blood; D000818:Animals; D001682:Biological Availability; D024402:Carbonic Anhydrase II / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D004952:Esters / Q000737:chemistry; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010052:Ovariectomy; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013449:Sulfonamides / Q000737:chemistry; D013923:Thromboembolism; D014599:Uterus / Q000187:drug effects
chemical_list: D004952:Esters; D004967:Estrogens; D011355:Prodrugs; D013449:Sulfonamides; D000808:Angiotensinogen; D004958:Estradiol; D002784:Cholesterol; D024402:Carbonic Anhydrase II
keywords: COC (combined oral contraceptives); Deep vein thrombosis; ERT (estrogen replacement therapy); Estradiol prodrug; Estradiol-17β sulfonamide esters