Improved Biomembrane Permeability Passive Diffusion

Due to the large surface area of the gastrointestinal epithelium, transcellular (passive) diffusion is a very important absorption principle for drug molecules. Thus, the ability of a compound to permeate this epithelium is of vital importance for the absorption of the drug. Transcellular diffusion of a compound is governed by its ability to interact with lipophilic cell membranes, and, thus, its lipophi-licity (Figure 9.7). This has been utilized in many prodrug strategies adding lipophilic promoieties to hydrophilic drug molecules or lead compounds. A few examples are given in the following text.

Pivampicillin, talampicillin, and bacampicillin are the pivaloyloxymethyl, the phthalidyl, and the ethoxycarbonyloxyethyl esters, respectively, of the parent penicillin ampicillin (Figure 9.9). These esters offer a significant increase in lipophilicity in comparison with the parent ampicillin by blocking the carboxylic function and adding lipophilic groups to the molecule.

As it appears from Figure 9.10, the prodrug strategy for pivmapicillin involves a double ester in which an initial enzymatic-mediated process is followed by a fast and spontaneous reaction. This principle has been successfully used to improve the oral bioavailability of ampicillin from about 30%-40% to essentially complete absorption. Thus, by employing the prodrug principle, unab-sorbed drug that may negatively interact with bacteria in the gastrointestinal tract will be significantly limited for the benefits of patients receiving the drug.

A major problem in the use of the b-adrenergic antagonist timolol (Figure 9.11) in the treatment of glaucoma is the high incidence of cardiovascular and respiratory side effects. This is due to absorption of the topically applied drug into the systemic circulation, which again can be attributed to insufficient corneal penetration of the drug. The use of more lipophilic prodrugs has been investigated to improve the corneal penetration of timolol and it was found that 0-butyryl timolol, which is 50 times more lipophilic than timolol (Figure 9.11), was absorbed into the aqueous humor


ch3 ch,




Ampicillin Pivampicillin Bacampicillin Talampicillin

FIGURE 9.9 Ampicillin, pivampicillin, talampicillin, and bacampicillin.


COO — CH2O - COC(CH3)3 Pivampicillin

+ HOOCC(CH3)3 CO° CH2OH Pivalic acid


+ H2CO COOH Formaldehyde


FIGURE 9.10 Biotransformation of pivampicillin.

0 1

/ 2

— CH — CH2 — NH — C(CH3)3


\ N



Log D
















FIGURE 9.11 Timolol and its O-alkyl esters.

four to five times better than timolol, while yielding similar plasma timolol concentrations. In addition to this, it has been shown that the 0-butyryl timolol prodrug offers extended duration of action in comparison with the parent timolol in an experimental animal model. This is most likely due to the more lipophilic prodrug being held in the ocular tissue compartment, which may act as a depot from which the drug is being slowly released. It should, however, be noted that although the 0-butyryl timolol ester and other alkyl esters indeed increase corneal absorption they at the same time suffer from chemical instability in aqueous solution. However, the chemical stability could be substantially improved by introducing sterically hindered esters such as the 2-ethylbutyryl, 3,3-dimethylbutyryl, and cyclopropanoyl derivatives.

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