Prodrugs

Prodrugs are pharmacologically inactive or less active derivatives of active drugs that are designed to be converted into the active compound in the body. The prodrug approach aims to improve properties such as solubility, permeability, stability, bioavailability, or tissue targeting, while reducing undesirable effects. Activation typically occurs through metabolic processes, often enzyme-catalyzed hydrolysis, reduction, or oxidation, and can involve other biochemical transformations or even gut microbiota.

Classification of prodrugs includes carrier-linked prodrugs, where a promoiety or carrier is covalently attached to the drug by a cleavable linker, and bioprecursors, where no discrete promoiety is present and the active drug is formed by metabolic transformation. Common activation mechanisms include ester or carbonate hydrolysis by carboxylesterases, amidases, or phosphatases; as well as reductions and oxidations mediated by hepatic or extrahepatic enzymes.

Examples illustrate various design goals: enalapril is hydrolyzed to the active ACE inhibitor enalaprilat; valacyclovir improves oral bioavailability of acyclovir; clopidogrel is converted by cytochrome P450 enzymes to active thiol metabolites; capecitabine is metabolized to 5-fluorouracil; oseltamivir is converted to oseltamivir carboxylate; codeine is metabolically converted to morphine to exert analgesic effects.

Applications include enhancing oral absorption, enabling taste masking or improved stability, reducing gastric irritation, and achieving tissue-specific activation or altered pharmacokinetics. Limitations encompass interindividual variability in activation, potential for incomplete or off-target metabolism, possible drug–drug interactions affecting activating enzymes, and added synthesis and regulatory complexity.