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

P. Mendes, S. G. Oliver, D. B. Kell

    Research output: Contribution to journalArticlepeer-review

    170 Downloads (Pure)

    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.
    Original languageEnglish
    Pages (from-to)710-723
    Number of pages13
    JournalTrends in pharmacological sciences
    Volume36
    Issue number11
    DOIs
    Publication statusPublished - Nov 2015

    Keywords

    • transporter drug verapamil phospholipid transmembrane propranolol metformin tuberculosis transcriptomics proteomics atenolol, metoprolol talinolol

    Fingerprint

    Dive into the research topics of 'Fitting transporter activities to cellular drug concentrations and fluxes: why the bumblebee can fly'. Together they form a unique fingerprint.

    Cite this