Prodrug research: futile or fertile?

The objective of this Commentary is to help clarify and illustrate what prodrugs are, what they are not, which benefits they can offer, and what their limits are. To this end, a number of criteria of classification and evaluation are presented. This is followed by a discussion of the pharmaceutical, pharmacokinetic and pharmacodynamic objectives of prodrug research. Recent examples (e.g. oseltamivir, bambuterol, capecitabine, clopidogrel and tirapazamine) are discussed in a biochemical perspective to illustrate these objectives and to demonstrate some of the therapeutic benefits afforded by successful prodrugs. Attention is also called to the fact that the in vitro and in vivo behavior of prodrug candidates may differ from that of the parent drug in ways that go beyond the original pharmaceutical, pharmacokinetic or pharmacodynamic objective being pursued. We conclude that prodrugs offer a viable strategy to disentangle pharmacodynamic and pharmacokinetic optimization.