Prodrugs: bridging pharmacodynamic/pharmacokinetic gaps

doi:10.1016/j.cbpa.2009.04.620

Current Opinion in Chemical Biology

Volume 13, Issue 3, June 2009, Pages 338-344

https://doi.org/10.1016/j.cbpa.2009.04.620 Get rights and content

In this mini review, prodrugs are discussed with a focus on their pharmaceutical, pharmacokinetic, and pharmacodynamic objectives, as well as on the resulting therapeutic benefits. Carrier-linked prodrugs remain the most extensively investigated and receive due attention here with recent successes highlighted. A clear trend is apparent in modern prodrug research, namely the increased attention given to the knowledge-based design of bioprecursors, namely prodrugs devoid of a detachable promoiety. In most cases, such prodrugs are activated by in situ reduction, hence their designation as bioreductive prodrugs. This is a particularly active field in the design of more selective, small-molecule antitumor agents. New antimicrobial agents are also in the pipeline. In addition, biooxidative bioprecursors offer a promising strategy in specific cases, as illustrated by the successful antiaggregating agent clopidogrel.

Introduction

What makes prodrugs different from other drugs is the fact that they are devoid of intrinsic pharmacological activity [1•, 2••, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]. Thus, the simplest and clearest definition, in this writer's view, is that given by Albert [16], who coined the term. In modified form, the definition reads: ‘Prodrugs are chemicals with little or no pharmacological activity, undergoing biotransformation to a therapeutically active metabolite.’

Drug discovery projects are in danger of failure should pharmacodynamic (PD) and pharmacokinetic (PK) prerequisites prove chemically incompatible that is impossible to combine in a single molecule. Because prodrugs and their active metabolite have different chemical structures, they must differ in their biological behavior, a fact that opens the door to dissociating PD and PK properties.

Section snippets

Why prodrugs?

The prodrug concept has found a number of useful applications in drug research and development. These correspond to a number of objectives, as presented in Figure 1. However, it should be clear that such a view is too schematic, these objectives being often intertwined. Thus, an improved solubility can greatly facilitate oral absorption, while improving the chemical stability of an active agent can allow tissue-selective delivery and even lead to its in situ activation.

How prodrugs?

Given the stated objectives, how can medicinal chemists design clinically useful prodrugs? As implicit above, two main classes of prodrugs exist, namely the carrier-linked prodrugs and the bioprecursors [3].

In carrier-linked prodrugs, the active agent (the drug) is linked to a carrier (also known as a promoiety). In many cases, carrier-linked prodrugs are esters activated by enzymatic hydrolysis, although nonenzymatic hydrolysis may contribute [11]. The variety of ester prodrugs in the

Conclusion

The gain in therapeutic benefit provided by prodrugs relative to the active agent is a question that knows no general answer. Depending on both the drug and its prodrug, the therapeutic gain may be negligible, modest, marked, or even significant. Nevertheless, a trend is apparent from innumerable data in the literature and when comparing marketed drugs and candidates in R&D. In the case of marketed drugs endowed with useful qualities but displaying some unwanted property (post hoc design), the

Conflicts of interest

None.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

References (41)

Testa B: Prodrug objectives and design. In ADME-Tox Approaches. Edited by Testa B, van de Waterbeemd H. Volume 5 in...
R.L. Mackman et al.
Prodrug strategies in the design of nucleoside and nucleotide antiviral therapeutics
Annu Rep Med Chem
(2004)
K. Beaumont et al.
Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: challenges to the discovery scientist
Curr Drug Metab
(2003)
A. Nemirovski et al.
Reduction of cis,trans,cis-[PtCl₂(OCOCH₃)2(NH₃)₂] by aqueous extracts of cancer cells
J Med Chem
(2007)
Testa B, Krämer SD: The biochemistry of drug metabolism—an introduction. Part 5. Metabolism and bioactivity. Chem...
J. Raito et al.
Prodrugs: design and clinical applications
Nat Rev Drug Discov
(2008)
C.G. Wermuth
Designing prodrugs and bioprecursors
B. Testa
Prodrugs
D.A. Smith
Do prodrugs deliver?
Curr Opin Drug Discov Dev
(2007)

B. Testa

Prodrug research: futile or fertile?

Biochem Pharmacol

(2004)

P. Ettmayer et al.

Lessons learned from marketed and investigational prodrugs

J Med Chem

(2004)

B. Testa et al.

Hydrolysis in Drug and Prodrug Metabolism — Chemistry, Biochemistry and Enzymology

(2003)

W. Wang et al.

Prodrug approaches in the improved delivery of peptide drugs

Curr Pharm Des

(1999)

H.J. Lee et al.

Recent advances in prodrugs and antedrugs

Curr Opin Drug Discov Dev

(1998)

D.A. Bradley

Prodrugs for improved CNS delivery

Adv Drug Deliv Rev

(1996)

A. Albert

Chemical aspects of selective toxicity

Nature

(1958)

Y. Hayashi et al.

A novel approach of water-soluble paclitaxel prodrug with no auxiliary and no byproduct: Design and synthesis of isotaxel

J Med Chem

(2004)

M. Skwarczynski et al.

No auxiliary, no byproduct strategy for water-soluble prodrugs of taxoids: scope and limitation of O–N intramolecular acyl and acyloxy migration reactions

J Med Chem

(2005)

G.L. Amidon et al.

A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability

Pharm Res

(1995)

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Prodrugs: bridging pharmacodynamic/pharmacokinetic gaps

Introduction

Section snippets

Why prodrugs?

How prodrugs?

Conclusion

Conflicts of interest

References and recommended reading

Annu Rep Med Chem

Curr Drug Metab

J Med Chem

Prodrugs: design and clinical applications

Nat Rev Drug Discov

Designing prodrugs and bioprecursors

Prodrugs

Do prodrugs deliver?

Curr Opin Drug Discov Dev

Prodrug research: futile or fertile?

Biochem Pharmacol

Lessons learned from marketed and investigational prodrugs

J Med Chem

Hydrolysis in Drug and Prodrug Metabolism — Chemistry, Biochemistry and Enzymology

Prodrug approaches in the improved delivery of peptide drugs

Curr Pharm Des

Recent advances in prodrugs and antedrugs

Curr Opin Drug Discov Dev

Prodrugs for improved CNS delivery

Adv Drug Deliv Rev

Chemical aspects of selective toxicity

Nature

A novel approach of water-soluble paclitaxel prodrug with no auxiliary and no byproduct: Design and synthesis of isotaxel

J Med Chem

No auxiliary, no byproduct strategy for water-soluble prodrugs of taxoids: scope and limitation of O–N intramolecular acyl and acyloxy migration reactions

J Med Chem

A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability

Pharm Res