Design Of Prodrugsapplication Of The Prodrug Principle

The prodrug principle offers an opportunity for optimization of drug therapy for a variety of reasons. The intention of this section is to illustrate important features of the principle by providing selected examples of achievements by prodrug design and development.

9.4.1 Design of Prodrugs with Improved Bioavailability

The oral bioavailability (F) of a compound is determined by a number of parameters such as aqueous solubility (determines the amount of drug available at the site of absorption), permeability (the ability of the molecule to permeate biological membranes), and stability in the gastrointestinal tract.

The relationship between lipophilicity—as measured by the distribution coefficient (D) between n-octanol and aqueous buffer at physiological pH—and the biomembrane permeability characteristics—as measured by the permeability coefficient (Papp) across, e.g., Caco-2 cell monolayers, i.e., the absorption (A) and the oral bioavailability (F), respectively, is shown in Figure 9.7.

It appears that the biomembrane permeability (Papp) increases with increasing lipophilicity until a certain point where the permeability is no longer controlled by the rate at which a given molecule permeates the cell layer and from where no further significant improvement can be induced. However, the mass transport that can be obtained (i.e., the flux) and thereby the oral absorption (A) and the bioavailability (F) tend to level off (illustrated by the shaded area in Figure 9.7) as the increase in lipophilicity continues. This is due to the fact that an increase in lipophilicity often dictates a significant decrease in aqueous solubility and thereby limiting the amount of drug available for absorption (i.e., limiting the concentration gradient that can be obtained) and, consequently, decreasing oral absorption and bioavailability. In addition to this, increased lipophilicity, in general, promotes the affinity to proteins such as enzymes and, thus, decreases the metabolic stability of the compounds and thereby increases systemic clearance leading to decreased oral bioavailability.

Thus, increasing the lipophilicity of drug compounds is advantageous in terms of oral bioavail-ability as long as it is not at the "expense" of aqueous solubility or other important parameters for drug absorption.


Solubility ^ => Flux ^ => Absorption ^ => Effect ^ Interaction with proteins => Metabolism => Clearance


Flux/absorption bioavailability

Flux/absorption bioavailability

Log D

FIGURE 9.7 Relationship between lipophilicity (D) and (1) biomembrane permeability (Papp), (2) absorption (A), and (3) oral bioavailability (F).

This is in agreement with Fick's first law of diffusion that describes the rate of diffusion across a (bio)membrane:

where dQ/dt is the mass flux across the membrane

A is the membrane surface area

C - Co determines the initial concentration gradient between the apical and basolateral side of the epithelium

Papp is the permeability coefficient

From this relationship, it follows that drug transport across the epithelium is governed by both aqueous solubility (generating a high initial concentration gradient) and permeability characteristics of the compound.

Thus, optimization of the flux and thereby the absorption potential is a balance between high aqueous solubility and adequate permeability characteristics. This has been successfully obtained by using the prodrug approach.

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