Improved Transporter Mediated Permeability

Various active transport mechanisms for amino acids, small peptides, monocarboxylic acids, monosaccharides, and nucleosides exist in the human body and it is generally recognized that such mechanisms play a major role in the absorption of many drug molecules. This has been used in prodrug design attempting to provide chemical bioreversible modifications mimicking natural substrates for various active transporters with the aim of improving intestinal absorption of various drugs.

The oral absorption of the antiviral compound gangciclovir (Figure 9.12) is less than 10%. Valgangciclovir, the corresponding L-valine ester of the compound, however, shows a marked increase in oral bioavailability of about 60%. This is mainly ascribed to the transport of the prodrug across the gastrointestinal epithelium, which is mediated by a small peptide active transport mechanism for which gangciclovir is not a substrate.

Another example of facilitating active absorption processes by the use of prodrugs is levodopa. Levodopa (or L-dopa) is a prodrug of the neurotransmitter dopamine and utilizes the L-aromatic amino acid transporter for permeation of the intestine and the blood-brain barrier. The active compound dopamine is regenerated by decarboxylation mediated by dopamine decarboxylase enzymes (Figure 9.13).

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