According to the original definition by Albert, prodrugs are a chemical with little or no pharmacological activity that undergoes biotransformation to the therapeutically active metabolite. Actually, the ‘activation’ of the prodrugs i.e. its conversion to the pharmacologically active form, may proceed under enzyme control, by non-enzymatic reaction, or by each of these in sequence. In general, the intention of the prodrugs approach is to improve the efficacy of an established drug. Prodrugs are developed to address numerous shortcomings, but probably most frequently to improve oral bioavailability, either by enhancing oral absorption or by reducing pre-systemic metabolism. As indicated in, transport of a drug through membranes, and hence its absorption, depends critically on the balance between the drug’s aqueous solubility and its lipophilicity.

Optimisation of this balance is often achieved by attaching a ‘carrier moiety’ to a polar group such as an acidic, alcoholic, phenolic or amino-function of the active species to yield the prodrug, which should then undergo predictable metabolism to release the active form in the body. Chemical derivatisation used to improve lipophilicity often involves conversion of acidic, phenolic and alcoholic functions into appropriate esters that are metabolized to the corresponding active drugs by esterases, which are ubiquitous. Aldehydes and ketones may be converted into acetals, and amines into quaternary ammonium species, amino acid peptides and imines. More recent developments involving prodrugs relate to their activation in two-step targeting therapies such as ADEPT (antibody-directed enzyme prodrug therapy) and GDEPT (gene-directed enzyme prodrug therapy).

These approaches hold particular promise in the area of cancer treatment through selective liberation of anticancer drugs at the surface of tumour cells. In contrast to the prodrugs described above, which are developed primarily to overcome pharmacokinetic problems, those used in ADEPT and GDEPT therapies are associated with site-specific drug delivery. Prodrug activation again relies on specific enzymes but in this case these are ‘predelivered’ to the desired sites of action. Several examples of relatively simple prodrugs are described first in this section. This is followed by a description of more complex systems that utilise prodrugs with the specific intention of site-specific delivery. A recent example of a successful prodrug is ximelagatran, which upon absorption is converted into its active metabolite melagatran, a potent competitive inhibitor of human α-thrombin.

 Melagatran was developed in the search for a new generation of oral anticoagulants with more predictable pharmacokinetic and pharmacodynamic properties than those of drugs in previous use, such as dicoumarol and warfarin. But despite having the necessary pharmacodynamic properties of a new antithrombotic agent, the oral bioavailability of melagatran was found to be only ~5%, which precluded its oral administration. This led to the development of its prodrug ximelagatran, produced by ethylation of the –COOH group and hydroxylation of the amidine group of the active compound. Poor bioavailability was attributed to the strong basic amidine functionality, originally selected in the design phase to fit the arginine side-pocket of thrombin. Hence this was replaced by the less basic N-hydroxylated amidine. In addition, an ethyl ester protecting group was introduced. Biotransformation of the prodrug to melagatran, involving ester cleavage and reduction of the amidoxime function, was demonstrated in vitro using microsomes and mitochondria from liver and kidney of pig and human.

Best Regards,
Nancy Ella
Associate Managing Editor
Drug Designing: Open Access