Editorial [Hot Topic: Prodrugs: Pharmaceutical Design and Current Perspectives (Executive Guest Editor: Josef Jampilek)]

Prodrug approaches become more and more important due to undesirable properties (poor bioavailability) of modern potential drugs. This problem can be solved by optimization of physico-chemical, biopharmaceutical or pharmacokinetic properties of the molecule, i.e. by design of prodrugs. Prodrugs are typically developed to overcome pharmaceutical, pharmacokinetic, and pharmacodynamic barriers. They are designed to maximize the amount of active drug that reaches its site of action. Prodrugs are converted into the active drug in the body through enzymatic or non-enzymatic reactions. The prodrug approach is characterized by a wide application spectrum: i) influencing bioavailability (increase of absorption/permeability by means of optimization of aqueous solubility and lipophilicity); ii) influencing duration of pharmacological effects (decrease of first-pass effect, increase of chemical/metabolic stability); iii) increasing site-specificity; iv) decreasing toxicity and various adverse/undesirable/irritation reactions; v) optimization of organoleptic properties; vi) improvement of drug formulation. Of all drugs worldwide, 5% are prodrugs; about 50% of prodrugs are activated by hydrolysis, 23% of prodrugs are activated by biotransformation, meaning there is no pro-moiety. Prodrugs hold a special position among structure (physico-chemical properties) modifications. General definition considers prodrugs as pharmacologically in vitro inactive derivatives of active drugs. Another proposed definition of prodrugs introduces the term “drug latentiation”, which means the chemical modification of a biologically active compound to form a new compound that, upon in vivo enzymatic attack, will liberate the parent compound [1,2]. Multiple classifying systems of prodrugs can be used, e.g. i) based on therapeutic categories (anticancer, antiviral, antibacterial, nonsteroidal anti-inflammatory, cardiovascular prodrugs, etc.); ii) based on the categories of chemical linkages or moiety/carriers that attach to the active drug (esteric, glycosidic, bipartite, tripartite prodrugs, and/or antibody-, gene-, virus-directed enzyme prodrugs); or iii) based on functional categories using strategic approaches to circumvent deficiencies inherent to the active drug (prodrugs for improving site specificity, prodrugs to bypass high first-pass metabolism, prodrugs for improving absorption and prodrugs for reducing adverse effects). Other general classification divides prodrugs into two main classes: carrier prodrugs (a result of a temporary linkage of the active molecule with a transport moiety that is cleaved by a simple hydrolytic reaction at the correct moment) and bioprecursor prodrugs (generation of a new compound, which is a substrate for the metabolizing enzyme, producing a metabolite, which is the expected active principle). A recently published new classification approach to prodrugs is proposed based on their sites of conversion into the final active drug form. In this system, prodrugs are classified into Type I (subtypes IA, IB) or Type II (subtypes IIA, IIB, IIC). For Type I prodrugs conversion occurs intracellularly, whereas conversion of Type II prodrugs occurs extracellularly [1-3]. The “classical” prodrug approach implemented in medicinal chemistry includes only chemical modification of the structure, e.g. blocking various moieties or substitution by various protective groups, but the design of prodrugs can also be widely understood as modification in the course of pre-formulation or formulation process, i.e. technological modification by means of complexation with liposomes, cyclodextrins, polylactic acid, betaglucan, pectin and chitosan derivatives or connection of a certain solid/insoluble nanoparticle carrier both/either for increasing penetration through the biological membrane (GI tract absorption, BBB penetration) and/or for targeted drug biodistribution [2]....