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Glossary of Pharmacology 

Prodrug 

Definition: 

A drug that requires activation, generally by enzymatic and/or chemical biotransformationto have its therapeutic effect. The parent compound of a prodrug does not have significant if any therapeutic activity.



Relevance: 

The rationale for prodrugs is the ability to improve the active drug's pharmacokinetic and/or pharmacodynamic properties. The prodrug approach allows for the development of more stable compounds in the gastrointestinal tract or more soluble than the parent compound, improving its bioavailability (Najjar & Karaman, 2019). For example, pivampicillin, a prodrug of ampicillin, carries an ester group which increases its lipophilicity. This chemical modification increases ampicillin's bioavailability from 32-55% to 87-94% (Rautio et al., 2008). The prodrug approach can also improve the delivery of drugs to the central nervous system (e.g., L-dopa) and minimize side effects.  

Examples of prodrugs, their activation process and therapeutic effects: 

Pro-drug 

Active drug 

Activation process 

Key therapeutic use of the active drug 

Azathioprine 

6-mercaptopurine 

Non-enzymatic conversion 

antineoplastic 

Codeine 

Morphine 

CYP2D6-mediated metabolism 

analgesic  

Clopidogrel 

Thiol-derivative 

CYP2C19-mediated oxidation 

anticoagulant 

Enalapril 

enalaprilat 

hydrolysis 

anti-hypertensive  

L-dopa 

dopamine  

decarboxylation  

antiparkinsonian  

Prednisone 

prednisolone  

reduction  

anti-inflammatory 

Simvastatin 

beta-hydroxy acid metabolite 

hydrolysis 

Lipid-lowering drug  

Sulfasalazine 

5-aminosalicylic acid 

Bacteria-mediated metabolism  

anti-inflammatory 

For a more comprehensive list of prodrugs, please refer to (Najjar & Karaman, 2019). 

Teaching tips:  

The concept of a prodrug can be used to teach about:

  • the impact of the pharmacokinetic processes on plasma drug concentration 
  • factors that affect bioavailability  
  • rational design and drug development  

Tricky points: 

How do you measure the bioavailability of prodrugs?

Suggested articles on this topic: 

  • Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Järvinen, T., & Savolainen, J. (2008). Prodrugs: design and clinical applications. Nature reviews. Drug discovery, 7(3), 255–270.  
      • This article provides an overview of the design strategies and clinical applications of prodrugs. It offers several examples of prodrugs and the rationale for their chemical modifications. It also explores how prodrug strategies can improve the pharmacokinetic properties of a targeted drug.  
    • Najjar, A., & Karaman, R. (2019). The prodrug approach in the era of drug design. Expert opinion on drug delivery, 16(1), 1–5.  
      • This summarized review provides several examples of prodrugs and prodrug strategies used in rugs approved by the FDA.

Linked terms: Parent drug, metabolism, drugs, bioavailability 

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