Danazol Amino Acid Prodrugs: In Vitro and in Situ Biopharmaceutical Evaluation

Three amino acid esters of danazol were evaluated to discern their potential as prodrugs to deliver high danazol concentrations to the systemic circulation. A different oral delivery mechanism was found for each of three danazol esters (lysinate, glycinate and sarcosinate) based upon hydrolysis data in biological fluids, enzymes, and portal vein and systemic concentrations following intraduodenal bolus doses and liver perfusions. Danazol lysinate was rapidly hydrolyzed to droplets of danazol in the intestinal fluid resulting in dose proportional absorption of danazol into the portal system. Danazol glycinate precipitates as amorphous particles in the intestinal tract where it is readily absorbed and partially hydrolyzed during absorption and by the liver resulting in both danazol and its glycinate being present in portal and systemic plasma. Danazol sarcosinate forms ester droplets in the intestinal tract which are very slowly hydrolyzed by intestinal enzymes. However, all of the sarcosinate ester is hydrolyzed during absorption resulting in only danazol being present in portal plasma. Each of the prodrugs, as oral dosages, resulted in increased systemic levels of danazol. This study clearly demonstrates how oral bioavailability can be improved with prodrugs, how metabolic mechanisms for prodrugs can be determined, how some animal models can mimic human drug disposition, how with three simple aminoacid esters, species differences can be demonstrated and what large differences can occur in physical form and hydrolytic reactivity.