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Fitting transporter activities to cellular drug concentrations and fluxes: why the bumblebee can fly

Pedro Mendes, Stephen G Oliver, Douglas B Kell

Trends in Pharmacological Sciences. 2015;36(11):710-723.

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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 â€Â˜randomlyâ€Â™ 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 â€Â˜randomâ€Â™ transporter could account for the flux 42% of the time, and that two transporters can achieve 10 · 10âˆÂ’6 cm·sâˆÂ’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 â€Â˜phospholipid bilayer diffusion (of drugs) is negligibleâ€Â™ is not disproved by the calculations of â€Â˜likelyâ€Â™ transporter-based fluxes.

Bibliographic metadata

Type of resource:
Content type:
Publication status:
Published
Publication type:
Publication form:
Published date:
Language:
eng
ISSN:
Volume:
36
Issue:
11
Start page:
710
End page:
723
Total:
13
Pagination:
710-723
Digital Object Identifier:
10.1016/j.tips.2015.07.006
Funding awarded to University:
  • BBSRC -
  • BBSRC - RESBBSRC
  • BBSRC -
Research data access statement included:
Yes
Attached files Open Access licence:
Creative Commons Attribution (CC BY)
Attached files embargo period:
Immediate release
Attached files release date:
15th December, 2015
Access state:
Active

Institutional metadata

University researcher(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:289828
Created by:
Pedrosa Mendes, Pedro
Created:
15th December, 2015, 16:17:00
Last modified by:
Pedrosa Mendes, Pedro
Last modified:
15th December, 2015, 16:17:00

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