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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review
  • Comment

MeSH terms

  • Animals
  • Cell Membrane Permeability*
  • Humans
  • Membrane Transport Proteins / metabolism*

Substances

  • Membrane Transport Proteins