Quantifying the impact of transporters on cellular drug permeability

•We examined the hypothesis that cellular drug permeability is mainly carrier mediated.•Drug permeability was simulated in the absence of passive transmembrane diffusion.•Analyses were based on transporter kinetics from the literature and global proteomics data.•The vast majority of simulated scenarios were consistent with the co-existence of transporters and transmembrane diffusion.

The conventional model of drug permeability has recently been challenged. An alternative model proposes that transporter-mediated flux is the sole mechanism of cellular drug permeation, instead of existing in parallel with passive transmembrane diffusion. We examined a central assumption of this alternative hypothesis; namely, that transporters can give rise to experimental observations that would typically be explained with passive transmembrane diffusion. Using systems-biology simulations based on available transporter kinetics and proteomic expression data, we found that such observations are possible in the absence of transmembrane diffusion, but only under very specific conditions that rarely or never occur for known human drug transporters.