Prodrugs for Enhancement of Lipophilicity


The capability of a drug to reverse a pathological condition on administration and elicit the desired pharmacological response is the ultimate goal of every drug therapy. This response is subject to bioavailability of the drug at the site of action, which is directly affected by the amount of drug in the blood. For a drug delivery system to be effective, it should be able to accomplish as well as sustain effective levels of drug in plasma. The route of a drug to its target site involves transport across a number of lipid membranes and hence membrane permeability or lipophilicity has a substantial impact on drug efficacy.

ILLUSTRATION 4.1 Applications of lipophilicity enhancement through prodrug approach.

Modification of hydrocarbon moieties of poorly permeable drugs results in increased lipophilicity. However, structure required for good activity is sometimes far from the structure required ideally for sufficient trans-membrane penetration. Under these circumstances the prodrug tool can prove be an enormously beneficial alternative. Enhancements of lipophilicity have been the most extensively explored and hence presently the most fruitful area of prodrug research. It has been accomplished by masking functional groups which are ionizable, nonionizable or polar in order to improve oral as well as topical absorption (e.g., especially in case of drugs that are usually administered by ocular and transdermal route) (Beaumont et al. 2003). Usually a hydrophilic carboxyl, thiol, phosphate, amine, or hydroxyl group present in the parent drug can be transformed to more lipophilic aryl or alkyl esters, and such prodrugs are then readily biocleaved by ubiquitous esterases (present throughout the body) to their active species (Liederer and Borchardt 2006). Several prodrug methodologies have been advanced for the polar phosphates, phosphonates and carboxylates; in most cases, conversion to prodrugs with ester group has been fruitful (Huttunen and Rautio 2011).

By employing prodrug strategy for lipophilicity enhancement, various drug-related issues like poor bioavailability, extensive pre-systemic metabolism, bitter taste, foul odor, short duration of action and drug-targeting have been successfully achieved (Illustration 4.1) (Rautio et al. 2008). These applications have been discussed section-wise in this chapter.

Prodrugs for Enhancement of Oral Bioavailability

In the field of discovery of a new chemical entity and its consequent development, oral bioavailability is one of the crucial considerations. It is widely accepted that poor oral bioavailability is one of the foremost causes of variability in therapeutics which in turn depends upon the differences observed in the amount of drug that is exposed. This is predominantly significant for drugs with lower therapeutic index or drugs with capability for development of resistance (cytotoxic drugs and antibiotics) (Bardelmeijer et al. 2008). Hellriegel et al. (1996) reported that “oral bioavailability of drugs from several therapeutic classes and the coefficient of inter-individual variability in their oral bioavailability are inversely proportional to each other” (Hellriegel et al. 1996). Unfortunately, poor oral bioavailability restricts the selection of oral route of administration of several drugs and in many cases considerable window is kept for losses in the dosage regimen design. As evident from the number of cases, more than 90% of drug after administration is lost to pre-systemic metabolism. Poor control of therapeutic effects and plasma concentrations and high extent of differences are outcome of low oral bioavailability. Especially, poor oral bioavailability is progressively a hurdle in the dosage regimen design as well as drug discovery process.

Oral bioavailability is a product of portion absorbed, portion bypassing excretion through liver and gut- wall; and the factors that impact bioavailability may be classified into biopharmaceutical factors, physiological, and physicochemical. It has been well recognized that oral absorption and drug metabolism is determined by physicochemical properties. The “rule-of-five” conceived by Lipinski and coworkers introduced an important breakthrough, displaying that compounds within certain physicochemical dimensions were bound to be clinically more significant than others (Abrahamsson and Lennernas 2005).

Bioavailability of a drug can be influenced by wide range of factors. Generally, three principal factors govern the availability of the drug and/or metabolite to the target receptor or organ, these are as follows:

  • 1. The speed and concentration of drug released from its formulation, and its subsequent absorption.
  • 2. The first-pass metabolism during its passage through the liver following absorption.
  • 3. The cumulative effect of drug distribution to different body fluids, plasma protein binding, metabolism and excretion (Brahmankar and Jaiswal 2006).

Application of prodrug strategy in enhancing lipophilicity and consequently overcoming bioavailability issues by minimizing first-pass metabolism and facilitating biological membrane permeation have been discussed in detail here. Prodrugs that increase lipophilicity by transiently masking the charge are employed for the enhancement of permeability of molecules. Active consideration of prodrug approach is crucial for researchers working in the field of drug discovery and development as it can yield candidates with anticipated pharmacokinetic and pharmaceutical properties. Advantages versus disadvantages of prodrug approach are shown in Illustration 4.2 (Baudy et al. 2009, Landowski et al. 2006, Donghi et al. 2009. Prichard et al. 2008, Ulrika et al. 2008).

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