A prodrug is a medication that is inactive or only weakly active when taken, but becomes active after it is converted inside the body. The idea behind a prodrug is simple: if the original drug has problems such as poor absorption, low solubility, irritation, or short duration, a modified version (prodrug) can overcome these issues and later release the active drug after metabolism.
Introduction
The term “prodrug” was first used by Adrian Albert in 1958. Many drugs struggle to reach their site of action due to poor stability, low absorption, or rapid breakdown. By giving a prodrug instead of the active drug, we can improve its delivery, safety, and effectiveness. Once inside the body, enzymes convert the prodrug into the active form.
What is a Prodrug?
A prodrug is a chemically modified, inactive compound that undergoes biotransformation to release the active drug. The process of designing such molecules is called drug latentiation. This transformation helps improve membrane transport, solubility, taste, targeting, and stability.
Advantages of Prodrugs
- Better absorption: Improves solubility and membrane permeability.
- Improved patient comfort: Taste masking, painless administration.
- Targeted action: Converts to active drug at the target tissue.
- Reduced toxicity: Lowers irritation and systemic side effects.
- Protection from degradation: Prevents breakdown in stomach or liver.
- Extended duration: Modified metabolism prolongs drug action.
- Better formulation options: Allows improved dosage forms.
Characteristics of an Ideal Prodrug
- Inactive or less active until converted inside the body.
- Contains a link that breaks easily to release the active drug.
- Releases non-toxic byproducts.
- Rapid and efficient conversion at the target site.
- Metabolites should be safe and easily excreted.
Classification of Prodrugs
A. Based on Structural Association
1) Carrier-Linked Prodrugs
The active drug is attached to a carrier molecule. After metabolism, the carrier is removed to release the drug.
- Bipartite prodrugs: A single carrier attached to the drug.
Example: Tolmetin–Glycine prodrug. - Tripartite prodrugs: Carrier connected via a linker for more design flexibility.
- Mutual prodrugs: Two active drugs are linked, each acting as a carrier for the other.
Example: Benorylate (aspirin + paracetamol).
2) Bioprecursor Prodrugs
These are inactive compounds converted into active drugs through enzymatic or chemical reactions.
Example: Prontosil → Sulfanilamide
B. Based on Site of Activation
- Type I (Intracellular)
- Type IA – Activated at target tissue (e.g., Acyclovir)
- Type IB – Activated in metabolic tissues like liver (e.g., Heroin → Morphine)
- Type II (Extracellular)
- Type IIA – Activated in GI fluids (e.g., Loperamide oxide)
- Type IIB – Activated in blood (e.g., Aspirin)
- Type IIC – Enzyme-targeted activation near the disease site (e.g., ADEPT system)
Carrier Linkages for Functional Groups
1. Carboxylic Acids and Alcohols
These groups are often converted into esters. Esterases in the body convert them back to active drugs.
Examples:
- Pivampicillin, Talampicillin, Bacampicillin – Prodrugs of ampicillin with improved absorption.
- Enalapril – Ethyl ester prodrug of enalaprilat, improving oral absorption.
2. Amines
Amines can be modified into amides or Mannich bases to improve stability.
Example: Hetacillin (prodrug of ampicillin)
3. Azo Linkages
Amino groups can form azo compounds useful for colon-specific delivery.
Example: Prontosil
4. Carbonyl Compounds
Aldehydes and ketones form derivatives that release the active drug on hydrolysis.
Example: Methenamine (releases formaldehyde in urine)
Detailed Notes:
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