Prodrugs for Improved Drug Delivery: Lessons Learned from Recently Developed and Marketed Products.

Milica Markovic,Arik Dahan,Shimon Ben-Shabat

doi:10.3390/pharmaceutics12111031

Milica Markovic, Arik Dahan + Show 1 more

Open Access

https://doi.org/10.3390/pharmaceutics12111031

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Journal: Pharmaceutics	Publication Date: Oct 29, 2020
Citations: 40	License type: CC BY 4.0

Affiliation: Ben-Gurion University of the Negev

Abstract

Prodrugs are bioreversible, inactive drug derivatives, which have the ability to convert into a parent drug in the body. In the past, prodrugs were used as a last option; however, nowadays, prodrugs are considered already in the early stages of drug development. Optimal prodrug needs to have effective absorption, distribution, metabolism, and elimination (ADME) features to be chemically stable, to be selective towards the particular site in the body, and to have appropriate safety. Traditional prodrug approach aims to improve physicochemical/biopharmaceutical drug properties; modern prodrugs also include cellular and molecular parameters to accomplish desired drug effect and site-specificity. Here, we present recently investigated prodrugs, their pharmaceutical and clinical advantages, and challenges facing the overall prodrug development. Given examples illustrate that prodrugs can accomplish appropriate solubility, increase permeability, provide site-specific targeting (i.e., to organs, tissues, enzymes, or transporters), overcome rapid drug metabolism, decrease toxicity, or provide better patient compliance, all with the aim to provide optimal drug therapy and outcome. Overall, the prodrug approach is a powerful tool to decrease the time/costs of developing new drug entities and improve overall drug therapy.

Highlights

Powerful modern drug discovery techniques, such as combinatorial chemistry and high-throughput screening, enable the discovery of novel chemical entities with high pharmacological efficacy [1]
We provide examples of potential uses and advantages of the contemporary prodrugs, such as overcoming solubility and permeability limitations, improving disease-targeting ability, overcoming extensive drug metabolism, and increasing treatment safety
Increasing knowledge of enzymes and membrane transporters in terms of structure, specificity toward different substrates, mechanism of action, and role can lead to the future development of successful targeted prodrug delivery

Summary

Introduction

Powerful modern drug discovery techniques, such as combinatorial chemistry and high-throughput screening, enable the discovery of novel chemical entities with high pharmacological efficacy [1]. The prodrug approach is used for the optimization of newly discovered chemical entities, as well as to improve the properties of already marketed drugs. The opportunity to control the mechanism and site of parent drug release from the prodrug, which, in turn, may enable targeting the free drug to the site(s) it is needed, presents a significant advantage for the modern prodrug approach and a challenge for the prodrug development; this step can be optimized through powerful computational simulations [19,20,21].

Results

Conclusion