Journal ArticleDOI
Implications of the dominant role of transporters in drug uptake by cells.
TLDR
Drug uptake is understood to be mainly transporter-mediated, which suggests that uptake transporters may be a major determinant of idiosyncratic drug response and a site at which drug-drug interactions occur.Abstract:
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.read more
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Journal ArticleDOI
Coexistence of passive and carrier-mediated processes in drug transport
Kiyohiko Sugano,Manfred Kansy,Per Artursson,Alex Avdeef,Stefanie Bendels,Li Di,Gerhard F. Ecker,Bernard Faller,Holger Fischer,Grégori Gerebtzoff,Hans Lennernaes,Frank Senner +11 more
TL;DR: The view is presented that both passive transcellular processes and carrier-mediated processes coexist and contribute to drug transport activities across biological membranes.
Journal ArticleDOI
Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples
TL;DR: This work highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure.
Journal ArticleDOI
Synthetic biology for the directed evolution of protein biocatalysts: navigating sequence space intelligently
TL;DR: Improving enzymes by directed evolution requires the navigation of very large search spaces; this work surveys how to do this intelligently.
Journal ArticleDOI
Lead-oriented synthesis: a new opportunity for synthetic chemistry.
TL;DR: Data is presented suggesting that much synthetic methodology is unintentionally predisposed to producing molecules with poorer drug-like properties, which may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger numbers of compounds from array techniques are prepared.
Journal ArticleDOI
The SLCO (former SLC21) superfamily of transporters
Bruno Hagenbuch,Bruno Stieger +1 more
TL;DR: This review tries to summarize what is currently known about OATPs with respect to endogenous substrates, tissue distribution, transport mechanisms, regulation of expression, structure-function relationship and mutations and polymorphisms.
References
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Journal ArticleDOI
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TL;DR: The ability of mass spectrometry to identify and, increasingly, to precisely quantify thousands of proteins from complex samples can be expected to impact broadly on biology and medicine.
Journal ArticleDOI
Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics.
Shao En Ong,Blagoy Blagoev,Irina Kratchmarova,Dan B. Kristensen,Hanno Steen,Akhilesh Pandey,Matthias Mann +6 more
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