EFFECTS OF 3-HYDRAZONE MODIFICATION ON THE METABOLISM AND PROTEIN-BINDING OF PROGESTERONE

Progesterone was rapidly metabolized with an apparent half-life of 2-2.5 min when incubated with isolated rat liver microsomes. Progesterone 3-hydrazone prodrugs, on the other hand, exhibited remarkable liver microsomal stability with apparent first-order half-lives increasing by about 35-350-fold over the parent drug. Protein binding experiments indicated significantly lower association of the prodrugs with human serum albumin as compared to progesterone. However, the combining affinities of the derivatives with α1-acid glycoprotein are comparable to that of progesterone itself. No appreciable binding of either progesterone or its produgs with other serum proteins, i.e., fibrinogen and γ-globulin, was observed. Therefore, 3-hydrazone prodrugs may be able to enhance oral absorption of progesterone not only by increasing its aqueous solubility but by reducing its first pass liver metabolism as well. © 1990.