Prodrugs: design and clinical applications

Key Points

  • Prodrugs are bioreversible derivatives of drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert its desired pharmacological effect.

  • The development of prodrugs is presently well established as a strategy for improving the physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically potent compounds and thereby overcoming barriers to a drug's developability and usefulness.

  • About 5–7% of the drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend.

  • Clinically, the majority of prodrugs are used with the aim of enhancing drug permeation by increasing drug lipophilicity and more recently to improve drug water solubility.

  • Site-selective drug delivery with reduced side effects, prevention of pre-systemic drug metabolism and the circumvention of efflux-limited drug absorption/distribution have not yet received enough attention in prodrug research, despite great possibilities.

  • This Review provides an overview of functional groups that are amenable to prodrug design, and highlights major applications of the prodrug strategy, including improving oral absorption, improving aqueous solubility, enhancing lipophilicity, enhancing active transport as well as achieving site-selective delivery.

Abstract

Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5–7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

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Figure 1: A simplified representative illustration of the prodrug concept.
Figure 2: Biopharmaceutical Classification System (BCS) characterization of drugs based on solubility and permeability measures.
Figure 3: Capecitabine as an example of a prodrug that requires multiple enzymatic activation steps.

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Biopharmaceutical Classification System

Glossary

Combinatorial chemistry

The rapid synthesis or the computer simulation of a large number of different but structurally related molecules.

Promoiety

A functional group used to modify the structure of pharmacologically active agents to improve physicochemical, biopharmaceutical or pharmacokinetic properties.

Co-drug

A chemical structure that undergoes conversion to two or more active drugs within a biological system, such conversion usually involves the metabolism of the co-drug.

Bioprecursor prodrug

A prodrug that does not contain a carrier or promoiety, but is metabolically or chemically transformed into an active drug.

Soft drug

Soft drugs are the opposite of prodrugs. They are active drugs that are designed to undergo a predictable and controllable deactivation or metabolism in vivo after achieving their therapeutic effect.

Bioconversion

A process in which the pharmacologically active drug is released or formed.

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Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255–270 (2008). https://doi.org/10.1038/nrd2468

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