A prodrug is a medication that is administered in an inactive or less active form and is converted into its active form within the body through enzymatic or chemical transformation. Prodrug design is a strategic approach in lead optimization to overcome pharmaceutical and pharmacokinetic barriers that limit the utility of active compounds.

Prodrugs are classified as Type I, where activation occurs intracellularly, or Type II, where activation occurs extracellularly. Carrier-linked prodrugs consist of the active drug attached to a promoiety that is cleaved by hydrolysis or enzymatic action. Bioprecursor prodrugs do not contain a promoiety but are activated through drug metabolism pathways such as oxidation or reduction.

Common prodrug strategies address poor aqueous solubility by adding ionizable or polar groups such as phosphate esters, amino acid esters, or hemisuccinate esters. The phosphate prodrug of prednisolone (prednisolone sodium phosphate) improves solubility for intravenous administration. Permeability limitations are addressed with lipophilic prodrugs such as ester derivatives of nucleoside analogs. Valacyclovir, the valine ester of acyclovir, has 3–5 times higher oral bioavailability.

Site-specific prodrugs target drug release to particular tissues or organs. Antibody-directed enzyme prodrug therapy (ADEPT) uses an antibody-enzyme conjugate localized at the tumor site to activate a systemically administered prodrug. Gene-directed enzyme prodrug therapy (GDEPT) delivers the activating enzyme gene to target cells.

The design of prodrugs requires that the promoiety is non-toxic, that the prodrug is stable during manufacturing and storage, and that the activation kinetics match the desired therapeutic profile. Esterases, phosphatases, and cytochrome P450 enzymes are the most common activating systems.