Enzyme-mediated activation of prodrugs

The development of potent drugs is always a challenging task and is often complicated by the number of pharmacokinetic and formulation limitations they suffer from. In addition, selectivity issues and targeting purposes make the regulatory approval a difficult-to-gain achievement. In this context, prodrugs strategy is widely employed and successful, especially, when a rational design is performed. Thus prodrugs are generated by introducing specific moieties or masking of already present chemical groups in the drug compounds in order to make them inactive or less active and allow a selective in vivo conversion into the corresponding active metabolites. The bioactivation process is mediated by chemical reactions due to the tissue microenvironment of the absorption or active site, e.g., the pH—acidic in the stomach or basic in the intestines—or reductive—in hypoxic cancers—or by the mediation of specific enzymes or classes of enzymes. Herein, we present an overview of enzymes involved in prodrugs activation, discussed according to the international enzyme classification (EC). Also, representative examples from the clinics are reported.