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Quantifying the impact of transporters on cellular drug permeability

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Highlights

  • We examined the hypothesis that cellular drug permeability is mainly carrier mediated.

  • Drug permeability was simulated in the absence of passive transmembrane diffusion.

  • Analyses were based on transporter kinetics from the literature and global proteomics data.

  • The vast majority of simulated scenarios were consistent with the co-existence of transporters and transmembrane diffusion.

The conventional model of drug permeability has recently been challenged. An alternative model proposes that transporter-mediated flux is the sole mechanism of cellular drug permeation, instead of existing in parallel with passive transmembrane diffusion. We examined a central assumption of this alternative hypothesis; namely, that transporters can give rise to experimental observations that would typically be explained with passive transmembrane diffusion. Using systems-biology simulations based on available transporter kinetics and proteomic expression data, we found that such observations are possible in the absence of transmembrane diffusion, but only under very specific conditions that rarely or never occur for known human drug transporters.

Section snippets

Alternative models explaining cellular drug permeability

The importance of transport proteins for the translocation of drugs across cell membranes has become increasingly appreciated over the past decades 1, 2. The predominant view of cellular drug transport is that such carrier-mediated transport coexists with diffusive transport across the lipid bilayers of cell membranes (Figure 1A) 3, 4. The relative importance of carrier-mediated transport and transmembrane diffusion will then differ depending on: (i) the chemical structure of the transported

How efficient does a transporter need to be to account for observations of high drug permeabilities?

Many drugs have high transcellular permeability (Box 2), either by design (e.g., to increase oral drug absorption and tissue distribution) or as a byproduct of the optimization of target affinity 3, 9, 10, 11. Classical examples include propranolol and verapamil. These have permeability coefficients across Caco-2 intestinal epithelial cell monolayers (the most commonly used cellular barrier for permeability studies) in the range 200–1000 × 10−6 cm/s 12, 13. Notably, the transcellular

Can transporters alone explain observations that define passive drug permeability?

When passive transmembrane diffusion dominates the transport across a cell monolayer, transport rates are expected to increase linearly with concentration and rates across a cell monolayer will be equal regardless of the transport direction [16] (Box 2). This behavior is often observed in vitro and linear absorption increases are common in dose-escalation studies of orally administered drugs 28, 29, 30. However, the absence of such concentration dependence and/or direction dependence does not

Concluding remarks

In conclusion, experimental observations consistent with passive transmembrane diffusion are not possible in the transporters-only model, unless the involved transporters fulfill specific criteria. The transporters would need to be highly efficient to account for the rates observed for high-permeability compounds. Unless the compounds ‘get stuck’ inside the cell, such transporters would be needed on both sides of the cellular barrier (e.g., in the apical and basolateral membranes of intestinal

Acknowledgments

The authors gratefully acknowledge assistance from Mr Amin Alimohammadi in the mining of literature transporter data. This work was supported by the Swedish Fund for Research without Animal Experiments, the Carl Trygger Foundation, and the Swedish Research Council (grant nos 9478 and 21386). L.A.F. was supported by the RPF Postdoctoral Fellowship Program from F. Hoffmann–La Roche, Basel, Switzerland.

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    Current address: CADD group, Eli Lilly UK, Erl Wood Manor, Windlesham, GU20 6PH, UK

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