Abstract
Prodrugs of β-estradiol (1) were prepared with the objective of improving its oral bioavailability. β-Estradiol-3-acetylsalicylate (2), β-estradiol-3-salicylate (3), and β-estradiol-3-anthranilate (4) were synthesized. With these prodrugs the 3-phenolic hydroxy group of estradiol was protected, so that first-pass conjugative metabolism could be reduced. Prodrug hydrolysis rates in dog and human plasma in vitro were determined. Deacetylation of estradiol-3-acetylsalicylate was much more rapid than its hydrolysis to estradiol. In dogs, oral estradiol bioavailability after administration of 2 and 4 was 17-fold and 5-fold higher, respectively, than after oral 1.
Similar content being viewed by others
REFERENCES
C. Longcope, S. Gorbach, B. Goldin, M. Woods, J. Dwyer, and J. Warram. J. Steroid Biochem. 23:1065–1070 (1985).
M. S. Powers, L. Schenkel, P. E. Darley, W. R. Good, J. C. Balestra, and V. A. Place. Am. J. Obstet. Gynecol. 152:1099–1106 (1985).
B. DeLignieres, A. Basdevant, G. Thomas, J.-C. Thalabard, C. Mercier-Bodard, J. Conrad, T.-T. Guyene, N. Mairon, P. Corvol, B. Guy-Grand, P. Mauvis-Jarvis, and R. Sitruk-Ware. J. Clin. Endocrinol. Metab. 62:536–541 (1986).
C. A. Mashchak, R. A. Lobo, R. Dozono-Takano, P. Eggena, R. A. Nakamura, P. F. Brenner, and D. R. Mishell, Jr. Am. J. Obstet. Gynecol. 144:511–518 (1982).
G. Falconi, F. Galletti, G. Celasco, and R. Gardi. Steroids 20:627–631 (1972).
B. J. Aungst, M. J. Myers, E. G. Shami, and E. Shefter. Int. J. Pharm. 38:199–209 (1987).
M. A. Hussain, C. A. Koval, M. J. Myers, E. G. Shami, and E. Shefter. J. Pharm. Sci. 76:356–358 (1987).
C. Longcope, D. W. Yesair, K. I. H. Williams, M. M. Callahan, C. Bourget, S. K. Brown, M. S. Carraher, C. Flood, and P. C. Rachwell. J. Steroid Biochem. 13:1047–1055 (1980).
O. A. T. Olsson and L.-Å Svensson. Pharm. Res. 1:19–23 (1984).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hussain, M.A., Aungst, B.J. & Shefter, E. Prodrugs for Improved Oral β-Estradiol Bioavailability. Pharm Res 5, 44–47 (1988). https://doi.org/10.1023/A:1015863412137
Issue Date:
DOI: https://doi.org/10.1023/A:1015863412137