Role of Transporters in Drug Absorption

These examples are unusual in that vaiacyciovir is an amino acid ester of a nucleoside that does not closely resemble the normal dipeptide substrates of the PEPT-1 transporter. A number of other drugs (such as methotrexate) are probably transported by proteins that normally transport the metabolites that they resemble and antagonize (e.g., folates). However, these cases represent fortuitous examples of drug transportability Tiatural selection during the drug discovery and development process. With increased understanding of the specificity determinants of 

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K. M., Role of organic cation transporters in drug absorption and... 

The apical localized sodium-dependent bile add transporter (ASBT) is expressed in the human duodenum and ileum and is barely detectable in colon [16]. ASBT transports bile adds such as glycodeoxycholate and chenodeoxycholic add (XX) [49, 50]. Few examples exist where the bile acid scaffold has been used as a promoiety for a prodrug approach. ASBT has micromolar affinities for the natural substrates, and the studies on ASBT are too few to make a general statement on the potential and role of this transporter in drug absorption [49, 50]. 

In recent years, there has been increasing awareness regarding the importance of transporters in the absorption and disposition of NMEs. While the major portion of NMEs or marketed drugs traverse cell membranes by passive diffusion, there are numerous examples where the involvement of specialized transport mechanisms has been demonstrated. Examples include the role of oligopeptide transporters in the intestinal absorption of P-lactam antibiotics, angiotensinconverting enzyme (ACE) inhibitors, and novel NMEs as well as the role of P-glycoprotein (P-gp) in the secretion of molecules into the intestine [11,77—79]. Transfection of cells with the transporter protein of interest has permitted the evaluation of precise cellular mechanisms of uptake and transport of NMEs. Transfected cell lines by definition are tailor-made to overexpress the protein of... 

Szakacs, G., Varadi, A., Ozvegy-Laczka, C, and Sarkadi, B. (2008) The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discovery Today. 13, 379-393. 

Zhang L, Brett CM, Giacomini KM. Role of organic cation transporters in drug absorption and elimination (review). Annual Rev Pharmacol Toxicol 1998 38 431-460. 

Suzuki, H., Sugiyama, Y., Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. Mini review, Ear. J. Pharm. Sci. 2000, 32, 3-12. 

Ayrton, A., Morgan, P., Role of transport proteins in drug absorption, distribution and excretion, Xenobiotica 2001, 31, 469-497. 

This volume gives an overview of the current status and an outlook to future more reliable predictive approaches. It is subdivided in five sections dealing with studies of membrane permeability and oral absorption, drug dissolution and solubility, the role of transporters and metabolism in oral absorption, computational approaches to drug absorption and bioavailability, and finally with certain drug development issues. 

This permeability barrier shows selectivity in that small hydrophobic molecules can partition into and diffuse across the lipid bilayer of the cell membrane, whereas small hydrophilic molecules can only diffuse between cells (i.e., through the intercellular junctions). In addition, the presence of uptake and efflux transporters complicates our ability to predict intestinal permeability based on physicochemical properties alone because transporters may increase or decrease absorptive flux. The complexity of the permeability process makes it difficult to elucidate permeability pathways in complex biological model systems such as animals and tissues. For this reason, cultured cells in general, and Caco-2 cells in particular, have been used extensively to investigate the role of specific permeability pathways in drug absorption. 

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