Trends in Pharmacological Sciences
OpinionQuantifying the impact of transporters on cellular drug permeability
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.
References (45)
Evidence-based approach to assess passive diffusion and carrier-mediated drug transport
Drug Discov. Today
(2012)Does transbilayer diffusion have a role in membrane transport of drugs?
Drug Discov. Today
(2012)What would be the observable consequences if phospholipid bilayer diffusion of drugs into cells is negligible?
Trends Pharmacol. Sci.
(2015)Caco-2 monolayers in experimental and theoretical predictions of drug transport
Adv. Drug Deliv. Rev.
(1996)Caco-2 permeability of weakly basic drugs predicted with the double-sink PAMPA pKa (flux) method
Eur. J. Pharm. Sci.
(2005)Enantioselective transport and CYP3A4-mediated metabolism of R/S-verapamil in Caco-2 cell monolayers
Eur. J. Pharm. Sci.
(2003)Epithelial transport of drugs in cell culture. I: a model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells
J. Pharm. Sci.
(1990)- et al.
The SLC2 (GLUT) family of membrane transporters
Mol. Aspects Med.
(2013) Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications
Mol. Aspects Med.
(2013)Comparison of drug transporter gene expression and functionality in Caco-2 cells from 10 different laboratories
Eur. J. Pharm. Sci.
(2008)
Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes
Cell
The SLCO (former SLC21) superfamily of transporters
Mol. Aspects Med.
Membrane transporters in drug development
Nat. Rev. Drug Discov.
Emerging transporters of clinical importance: an update from the International Transporter Consortium
Clin. Pharmacol. Ther.
Coexistence of passive and carrier-mediated processes in drug transport
Nat. Rev. Drug Discov.
Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule?
Nat. Rev. Drug Discov.
Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition
Mol. Pharm.
Drug-like property concepts in pharmaceutical design
Curr. Pharm. Des.
Lipophilicity in drug discovery
Expert Opin. Drug Discov.
Extensive quantitative remodeling of the proteome between normal colon tissue and adenocarcinoma
Mol. Syst. Biol.
Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers
Nat. Protoc.
Will the original glucose transporter isoform please stand up!
Am. J. Physiol. Endocrinol. Metab.
Cited by (0)
- *
Current address: CADD group, Eli Lilly UK, Erl Wood Manor, Windlesham, GU20 6PH, UK