2015 Volume 30 Issue 5 Pages 454-464
As sulfa drug was found as the urinary metabolite of Prontosil in past times, early prodrugs were often discovered by chance. The prodrugs later on, however, have been synthesized by chemically modifying the pharmacologically active substance, most frequently, with an intension of increased lipophilicity for an improved intestinal absorption and efficient enzymatic conversion to the active substance in the body. This could be achieved based on plenty of knowledge on the activating enzymes like esterases. In cases where the chemical structures of active metabolites or the mechanisms of metabolic activation are unknown, however, we cannot implement such strategies. The examples are the thienopyridine antiplatelet agents whose active metabolites have not been structurally clarified for long even though their clinical usefulness as the anti-platelet drugs has been well established in human studies. In this article, we describe the mechanisms for metabolic activation of thienopyridines and impact of the differenes in the activation mechanism on the clinical outcomes.
