title: Quantifying the impact of transporters on cellular drug permeability.
abstract: 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.
authors: Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden; Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala, Sweden; Science for Life Laboratory Drug Discovery and Development Platform, Uppsala University, Uppsala, Sweden. Electronic address: par.matsson@farmaci.uu.se.
authors: Pär
authors: P
authors: Matsson
authors: Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden; Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala, Sweden; Science for Life Laboratory Drug Discovery and Development Platform, Uppsala University, Uppsala, Sweden.
authors: Luca A
authors: LA
authors: Fenu
authors: Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden; Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala, Sweden; Science for Life Laboratory Drug Discovery and Development Platform, Uppsala University, Uppsala, Sweden.
authors: Patrik
authors: P
authors: Lundquist
authors: Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
authors: Jacek R
authors: JR
authors: Wiśniewski
authors: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors: Manfred
authors: M
authors: Kansy
authors: Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden; Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala, Sweden; Science for Life Laboratory Drug Discovery and Development Platform, Uppsala University, Uppsala, Sweden. Electronic address: per.artursson@farmaci.uu.se.
authors: Per
authors: P
authors: Artursson
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability; D006801:Humans; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D020543:Proteome / Q000235:genetics / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; D020543:Proteome
keywords: carrier-mediated transport; drug transport; passive diffusion; permeability; systems biology; transporter