A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug is absorbed, distributed, metabolized, and excreted (ADME).

Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract.

Note 2: Prodrugs can thus be viewed as drugs containing specialized nontoxic protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule.

History

Many herbal extracts historically used in medicine contain glycosides (sugar derivatives) of the active agent, which are hydrolyzed in the intestines to release the active and more bioavailable aglycone. For example, salicin is a β-D-glucopyranoside that is cleaved by esterases to release salicylic acid. Aspirin (acetylsalicylic acid), first made by Felix Hoffmann at Bayer in 1897, is a synthetic prodrug of salicylic acid. However, in other cases, such as codeine and morphine, the administered drug is enzymatically activated to form sugar derivatives (morphine-glucuronides) that are more active than the parent compound.

Approved prodrugs

Approximately 10% of all marketed drugs worldwide can be considered prodrugs. Since 2008, at least 30 prodrugs have been approved by the FDA. based on how the body converts the prodrug into the final active drug form:

  • Type I prodrugs are bioactivated inside the cells (intracellularly). Examples of these are anti-viral nucleoside analogs that must be phosphorylated and the lipid-lowering statins.
  • Type II prodrugs are bioactivated outside cells (extracellularly), especially in digestive fluids or in the body's circulatory system, particularly in the blood. Examples of Type II prodrugs are salicin (described above) and certain antibody-, gene- or virus-directed enzyme prodrugs used in chemotherapy or immunotherapy.

Both major types can be further categorized into subtypes, based on factors such as (Type I) whether the intracellular bioactivation location is also the site of therapeutic action, or (Type 2) whether or not bioactivation occurs in the gastrointestinal fluids or in the circulation system.

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|+Classification of prodrugs

See also

  • Hypoxia-activated prodrugs
  • Neurotransmitter prodrug
  • Precursor (chemistry)
  • Toxication

References

  • Special Issue on Prodrugs: from Design to Applications