Chapter 31. Prodrug Approach in Drug Design

Abstract

This chapter discusses the prodrug concept in the design of drugs with improved pharmaceutical, physicochemical, and biological properties. Two major factors are important in the design of prodrugs (1) determination of what physicochemical properties are required in order to eliminate the undesired effect in the parent molecule; and (2) selection of a chemical linkage that alters this effect. The chemical modification of a parent drug molecule to form its prodrug involves altering certain physicochemical properties of that molecule. Alteration of aqueous solubility of the parent molecule via the prodrug approach is the primary method, whereby bioavailability (absorption) is enhanced. The addition of lipophilic (hydrophobic) groups to a molecule frequently improves drug passive absorption through epithelial tissue and is because of the increase in the biological membrane-water partition coefficient. As most drug molecules are either weak acids or bases, dissociation and solubility of the drug in biological fluids and absorption are all interrelated phenomena. Usually the unionized form of a drug is absorbed more efficiently than its ionic specie and is because of the fact that the increase in the partition coefficient of the free acid or base vs. the prodrug derivative is much greater than the corresponding decrease in aqueous solubility. The chapter also discusses various types of prodrugs such as aliphatic-aromatic esters; carbonate esters; hemiesters; phosphate esters; and nitrate and sulfate esters.