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

Abstract

A recent paper in this journal argued that reported expression levels, k _cat and K _m 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.

Trends

There has been recent debate as to the relative extents to which cellular transmembrane drug transports occur through any phospholipid bilayer region or is transporter-mediated only.

Much recent evidence suggests (perhaps surprisingly) that phospholipid bilayer diffusion is negligible.

A recent article in this journal suggested that the expression profile and kinetics of known transporters might not be adequate to explain the most active drug fluxes (of verapamil and propranolol) in Caco-2 cells via transporters only.

We show with our own simulations that this is not in fact the case, especially when evolutionary selection is taken into account, and that the Haldane relation accounts straightforwardly for directional differences, even for equilibrative transporters.

Typical protein transporters alone can easily account for measured drug fluxes in Caco-2 cells.