Esterases involved in hydrolysis of prodrug and antedrug/soft drug

Abstract

The approach of prodrug and antedrug/soft drug is useful for resolving formulation, delivery, and toxicity limitations on problematic drugs. A prodrug is a pharmacologically inactive derivative of an active parent drug. The “ante drug” or “soft” drug have been designed to exert their desired effect locally but they are inactivated in the circulation to reduce unwanted systemic effects. Recently, both prodrug and antedrug/soft drug are becoming an integral part of the drug discovery paradigm. The metabolic consideration is most important in the design of prodrug and antedrug/soft drug. Since esterase is abundantly present in several tissues, most of prodrugs and antedrugs/soft drugs are metabolized by esterases and fully converted to their active and inactive metabolite. Prodrug aimed improvement of bioavailability of parent drug is activated by esterases in liver and intestine before entering systemic circulation, then enough high plasma concentration of parent drug results in an appropriate pharmacological effect. Antedrug/soft drug is mainly inactivated in blood and liver. Therefore, the design of prodrug and antedrug/soft drug hardly possible without understanding several esterases in intestine, liver and blood. This review introduces the example of prodrug and antedrug/soft drug and describes the important enzymes involved in prodrug activation and antedrug/soft drug inactivation notably with respect to substrate specificity, tissue distribution and species difference.