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Trends Pharmacol Sci. 2015 Jan;36(1):15-21. doi: 10.1016/ Epub 2014 Nov 10.

What would be the observable consequences if phospholipid bilayer diffusion of drugs into cells is negligible?

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School of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK. Electronic address:


For drug transport across (i.e., through) an intact biological membrane, two main routes are possible: drugs may cross (i) through the phospholipid bilayer portion of the membrane, and/or (ii) via proteinaceous pores or transporters. Perhaps surprisingly, there is in fact no direct scientific evidence that the first of these takes place at any significant rate because, in the experiments performed to date, it has neither been varied as an independent variable nor measured directly as a dependent variable. Using a standard hypothetico-deductive framework, I assess the intellectual and observable consequences of assuming that, for drugs, phospholipid bilayer diffusion is negligible - 'PBIN' - (i.e., may be neglected, relative to transporter-mediated transmembrane fluxes). Predictions and postdictions of the PBIN hypothesis are not refuted by available experimental evidence.


drug transporters; lipoidal bilayer diffusion; physiologically based pharmacokinetic modelling; systems pharmacology

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