Page - (000229) - in Biomedical Chemistry: Current Trends and Developments

for facilitating membrane transport of polar nutrients such as amino acids and peptides. There is direct and indirect evidence for the participation of carrier-mediated membrane transport mechanisms, where several hydrophilic compounds seem to be absorbed efficiently via specific transporters (Mizuma, 1992). Therefore, targeting specific membrane transporters is particularly important when prodrugs are polar or charged. From this point of view, use of intestinal epithelial transporters to facilitate the absorption of appropriately modified drugs seems to be an attractive strategy for improving the bioavailability of poorly absorbed drug molecules. Prodrugs can be designed to structurally resemble intestinal nutrients and to be absorbed by specific carrier proteins. In this case, prodrugs may have the additional advantage of producing nontoxic nutrient by products during conversion to the parent drug molecules. There have been many attempts to improve drug absorption targeting specific membrane transporters, including amino acid, peptide, and glucose transporters (Han & Amidon, 2000). To exemplify the utility of amino acid prodrugs targeted to transporters expressed in the gastrointestinal tract, gabapentin and baclofen are structural analogs of GABA (gamma amino butyric acid) used for the treatment of various neurological disorders. Both gabapentin and baclofen have structural features of amino acids. They are both absorbed in the upper small intestine by a low-capacity solute transporter localized in the upper small intestine, possibly an L-type amino acid transporter (Vig, 2013). XP13512 and XP19986 are novel prodrugs of gabapentin and baclofen, respectively, designed to overcome pharmacokinetic limitations of the parent drugs. Transport of these prodrugs is mediated by monocarboxylate transporter type 1 (MCT- 1) and sodium-dependentmultivitamin transporter (SMVT) (Cundy, 2004; Lal, 2009). L-type amino acid transporter 1 (LAT1) is a sodium-independent heterodimeric transmembrane protein found in brain, testis and placenta. The levels of functional LAT1 are also significantly up- regulated in the surface of several human tumour cells, highlighting its essential role in cell growth and proliferation. LAT1 is responsible for transporting large neutral amino acids such as L-Leu, L-Trp, L-Ile and L-