The Prodrug Principle

The term "prodrug" or "proagent" was introduced by A. Albert in 1958 to describe compounds that undergo biotransformation prior to eliciting a pharmacological effect.

As shown in Figure 9.2, the formation of a prodrug provides a transient change of physicochemi-cal and biological properties thereby altering or eliminating undesirable properties of the parent drug molecule. This prodrug to drug biotransformation may take place before absorption, during absorption, immediately after absorption, or at a specific site of action.

The conversion of prodrugs to the active parent drug molecule can take place through various reactions such as hydrolytic cleavage either as a spontaneous or enzyme-mediated reaction.




Chemical modification





FIGURE 9.2 The prodrug principle.

The prodrug approach has been successfully utilized to overcome significant barriers for many drugs aiming

1. To improve the oral bioavailability by increasing aqueous solubility, by increasing biomembrane permeability, and/or by improving (metabolic) stability

2. To increase the duration of pharmacological action

3. To decrease toxicity or adverse reactions

4. To obtain drug targeting using site-specific biotransformation or site specific transporters

The prodrug approach has been used over a span of more than three decades mainly as a means to address drugability problems with drugs already introduced to the market. The aim has primarily been to develop improved versions of such drugs or as a rescue for compounds with drugability problems in late-stage development; and several drugs have been developed and are used in clinical practice as prodrugs (e.g., pivampicillin, enalapril, and vanaciclovir). In modern drug design, prodrug strategies are considered part of the drug discovery effort aiming to expand the chemical space of drugable molecules and, thus, it can be expected that many future drugs will appear as prodrugs.

The purpose of this chapter is to introduce the reader to the prodrug principle and discuss important elements in prodrug strategies within drug discovery and development. Finally, we will provide examples of achievements offered by prodrugs.

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