A prodrug can be defined as a drug substance that is inactive in the intended pharmacological actions and is must to be converted into the pharmacologically active agent by metabolic or physico-chemical transformation.
A prodrug is formed by chemical modification of a biologically active drug that will liberate the active compound in vivo by enzymatic or hydrolytic cleavage. The objective of employing a prodrug is to increase drug absorption and to reduce side effects. Therefore, a prodrug is often classified as a controlled release dosage form.
Prodrugs which are more lipophilic than the parent drug can increase membrane penetration and thus drug absorption. For example, phenytoin 2-monoglycerides, a lipophilic phenytoin prodrug, afforded significant increase in oral absorption and bioavailability.
The prodrug form can protect the parent compound from hydrolysis or enzymatic attack. A series of ester prodrugs of proprandol protected the drug from first-pass metabolism. An example of a prodrug is enalapril maleate, which on oral administration is bioactivated by hydrolysis to enalaprilat, an angiotensin-converting enzyme (ACE) inhibitor used in the treatment of hypertension.
Prodrugs can exist naturally such as many phytochemicals/botanical constituents and endogenous substances, or they can result from synthetic or semisynthetic processes – produced intentionally as part of a rational drug design or unintentionally during drug development.
Examples of prodrugs that exist naturally or were produced unintentionally during drug development include aspirin, psilocybin, parathion, irinotecan, codeine, heroin, L-dopa, and various antiviral nucleosides.
Examples of products resulting from pharmaceutical processes as part of strategically targeted drug design include sulfasalazine, oseltamivir, various nonsteroidal anti-inflammatory drugs (ketoprofen, diclofenac), statins (lovastatin, simastatin), ACE inhibitors (captopril, lisinopril) and penicillin-related agents (bacampicillin, sarmoxicillin).
Rationale of prodrug formulations
Some useful active compounds have been formulated as prodrugs to surmount such problems as unpalatability, gastrointestinal irritation or pain on injection. Other prodrugs achieve greater solubility or stability than the active compound.
Several pharmacokinetic reasons exist for developing prodrugs:
- To achieve more complete or predictable absorption of the drug.
- To reduce incomplete and variable systemic bioavailability by preventing extensive presystemic metabolism.
- To improve access to the site of action, e.g. penetration of the blood-brain barrier.
- To activate selectively a drug in the intended target tissue, thus avoiding undesirable systemic effects.
- To optimise either the rate of onset or duration of action of a drug by improving absorption, distribution or elimination characteristics.