Hussain M A, Aungst B J, Shefter E
Du Pont Pharmaceuticals, Medical Products Department, Wilmington, Delaware 19898.
Pharm Res. 1988 Jan;5(1):44-7. doi: 10.1023/a:1015863412137.
Prodrugs of beta-estradiol (1) were prepared with the objective of improving its oral bioavailability. beta-Estradiol-3-acetylsalicylate (2), beta-estradiol-3-salicylate (3), and beta-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.
制备β-雌二醇（1）的前药是为了提高其口服生物利用度。合成了β-雌二醇-3-乙酰水杨酸酯（2）、β-雌二醇-3-水杨酸酯（3）和β-雌二醇-3-邻氨基苯甲酸酯（4）。通过这些前药，雌二醇的3-酚羟基被保护起来，从而可以减少首过结合代谢。测定了前药在犬和人血浆中的体外水解速率。雌二醇-3-乙酰水杨酸酯的脱乙酰化比其水解为雌二醇的速度快得多。在犬中，给予2和4后口服雌二醇的生物利用度分别比口服1后高17倍和5倍。
