Prodrugs: bridging pharmacodynamic/pharmacokinetic gaps
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...
- et al.
Prodrug strategies in the design of nucleoside and nucleotide antiviral therapeutics
Annu Rep Med Chem
(2004) - et al.
Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: challenges to the discovery scientist
Curr Drug Metab
(2003) - 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...
- et al.
Prodrugs: design and clinical applications
Nat Rev Drug Discov
(2008) Designing prodrugs and bioprecursors
Prodrugs
Do prodrugs deliver?
Curr Opin Drug Discov Dev
(2007)
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
Cited by (79)
Targeting microbiome, drug metabolism, and drug delivery in oncology
2023, Advanced Drug Delivery ReviewssmProdrugs: A repository of small molecule prodrugs
2023, European Journal of Medicinal ChemistryRecent advances in combretastatin A-4 codrugs for cancer therapy
2022, European Journal of Medicinal ChemistryStrategies and progresses for enhancing targeted antibiotic delivery
2022, Advanced Drug Delivery ReviewsCitation Excerpt :Prodrugs are inactive agents which are spontaneously or metabolically converted to their pharmacologically active forms inside the body [122]. This strategy avoids the shortcomings of existing antibiotics which are highly effective against resistant bacteria but possess poor pharmacokinetic properties [123]. Moreover, the prodrug approach can be employed for site-specific drug delivery and can assist in reducing side effects [124,125].
Novel strategies to improve tumour therapy by targeting the proteins MCT1, MCT4 and LAT1
2021, European Journal of Medicinal ChemistryEmerging insights on drug delivery by fatty acid mediated synthesis of lipophilic prodrugs as novel nanomedicines
2020, Journal of Controlled Release