Implications of the Dominant Role of Transporters in Drug Uptake by Cells (Supplementary Material)
Paul D. Dobson, Karin Lanthaler, Stephen G. Oliver and Douglas B. Kell
Affiliation: School of Chemistry and Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
Keywords: Systems Biology, drug transporter, drug uptake, pharmacokinetic modelling, Saccharomyces, cheminformatics
Drug entry into cells was previously believed to be via diffusion through the lipid bilayer of the cell membrane, with the contribution to uptake by transporter proteins being of only marginal importance. Now, however, drug uptake is understood to be mainly transporter-mediated. This suggests that uptake transporters may be a major determinant of idiosyncratic drug response and a site at which drug-drug interactions occur. Accurately modelling drug pharmacokinetics is a problem of Systems Biology and requires knowledge of both the transporters with which a drug interacts and where those transporters are expressed in the body. Current physiology-based pharmacokinetic models mostly attempt to model drug disposition from the biophysical properties of the drug, drug uptake by diffusion being thereby an implicit assumption. It is clear that the incorporation of transporter proteins and their drug interactions into such models will greatly improve them. We discuss methods by which tissue localisations and transporter interactions can be determined. We propose a yeast-based transporter expression system for the initial screening of drugs for their cognate transporters. Finally, the central importance of computational modelling of transporter substrate preferences by structure-activity relationships is discussed.
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