Prodrug

A prodrug carries no useful activity as administered and is metabolised in vivo into the active species. Carrier-linked prodrugs attach a removable group — commonly an ester, an amide or an amino acid — cleaved by esterases or peptidases, while bioprecursors are oxidised or rearranged into the active form without shedding a carrier. The strategy solves delivery problems the active molecule cannot: poor absorption, poor solubility, rapid clearance, or lack of tissue targeting.

Enalapril is hydrolysed to enalaprilat, which is poorly absorbed by mouth; valacyclovir is an amino acid ester that recruits an intestinal transporter to raise aciclovir absorption several-fold; lisdexamfetamine is dexamfetamine linked to lysine and cleaved in blood. In the hormone space the clearest cases are injectable esters such as testosterone cypionate and enanthate, whose duration is a property of the ester rather than the hormone.

Prodrug status changes what a measurement means. Concentrations of the administered compound may correlate poorly or not at all with effect, so exposure has to be assessed on the active metabolite. It also introduces a conversion step that varies: enzyme polymorphisms, hepatic or renal impairment, and interactions that inhibit or induce the activating enzyme all move the effective dose without changing the administered one.

The term is stretched to cover things it does not describe. A peptide fragment that is merely shorter than its parent is not a prodrug without a demonstrated bioactivation step producing a defined active species. Grey-market listings sometimes call research compounds prodrugs of approved hormones, which asserts both a conversion pathway and an equivalence, usually with no evidence for either.