Rationale for Prodrug Design

A large number of the new molecular entities with promising therapeutic profiles are dropped from the screening stage because of their inferior physicochemical and biopharmaceutical properties. These undesired properties result in poor absorption, extensive metabolism, and low bioavailability because of physical, biological, or metabolic barriers. If the chemical structure of the drug or lead compound can be modified to overcome these barriers and then revert to the pharmacologically active form, the drug can be delivered efficiently. The rationale for the design of prodrugs is to achieve favorable physicochemical characteristics (e.g., chemical stability, solubility, taste, or odor), biopharmaceutical properties (e.g., oral absorption, first-pass metabolism, permeability across biological membranes such as the blood-brain barrier, or reduced toxicity), or pharmacodynamic properties (e.g., reduced pain or irritation). The objectives in designing a prodrug are described in Table 3.1.

Meeting a single objective often addresses others; for example, improved solubility may simultaneously address low absorption and bioavailability and provide an improved plasma concentration-time

TABLE 3.1 Objectives in Prodrug Design

Pharmacodynamic objectives

Mask reactive species to improve its therapeutic index

Activate cytotoxic agent in situ

Pharmaceutical objectives

Improve solubility

Improve chemical stability

Improve taste, odor

Decrease irritation and pain

Pharmacokinetic objectives

Improve oral absorption

Decrease presystemic metabolism Improve absorption by nonoral routes Improve plasma concentration-time profile Provide organ/tissue-selective delivery of active agent source: Ref. 12.

profile. Thus prodrugs can be designed to achieve a myriad of objectives with significant overlaps.

Multiple benefits associated with prodrug design include increased bioavailability with ester prodrugs, increased permeability with hydroxyl amine prodrugs, enhanced solubility with prodrug salts, enhanced stability with PEGylated prodrugs, enhanced absorption with prodrugs targeted at intestinal transporters, and improved cancer therapy with gene- and receptor-targeted prodrugs.

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