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Trends Pharmacol Sci. 2015 Nov;36(11):710-723. doi: 10.1016/j.tips.2015.07.006. Epub 2015 Nov 1.

Fitting Transporter Activities to Cellular Drug Concentrations and Fluxes: Why the Bumblebee Can Fly.

Author information

1
School of Computer Science; Manchester Institute of Biotechnology, The University of Manchester, 131 Princess St, Manchester M1 7DN, UK; Centre for Synthetic Biology of Fine and Speciality Chemicals (SYNBIOCHEM), The University of Manchester, 131, Princess St, Manchester M1 7DN, United Kingdom; Center for Quantitative Medicine, University of Connecticut, UConn Health, 263 Farmington Avenue, Farmington, CT 06030-6033, USA.
2
Cambridge Systems Biology Centre; Dept of Biochemistry, University of Cambridge, Sanger Building, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
3
Manchester Institute of Biotechnology, The University of Manchester, 131 Princess St, Manchester M1 7DN, UK; Centre for Synthetic Biology of Fine and Speciality Chemicals (SYNBIOCHEM), The University of Manchester, 131, Princess St, Manchester M1 7DN, United Kingdom; School of Chemistry, The University of Manchester, Manchester M13 9PL, United Kingdom. Electronic address: dbk@manchester.ac.uk.

Abstract

A recent paper in this journal argued that reported expression levels, kcat and Km for drug transporters could be used to estimate the likelihood that drug fluxes through Caco-2 cells could be accounted for solely by protein transporters. It was in fact concluded that if five such transporters contributed 'randomly' they could account for the flux of the most permeable drug tested (verapamil) 35% of the time. However, the values of permeability cited for verapamil were unusually high; this and other drugs have much lower permeabilities. Even for the claimed permeabilities, we found that a single 'random' transporter could account for the flux 42% of the time, and that two transporters can achieve 10·10(-6)cm·s(-1) 90% of the time. Parameter optimisation methods show that even a single transporter can account for Caco-2 drug uptake of the most permeable drug. Overall, the proposal that 'phospholipid bilayer diffusion (of drugs) is negligible' is not disproved by the calculations of 'likely' transporter-based fluxes.

PMID:
26538313
PMCID:
PMC4642801
DOI:
10.1016/j.tips.2015.07.006
[Indexed for MEDLINE]
Free PMC Article

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