Multi drug resistance-dependent "vacuum cleaner" functionality potentially driven by the interactions between endocytosis, drug size and Pgp-like transporters surface density.

In cells, multi drug resistance (MDR) is associated with Pgp-like transporters expression extruding drugs from cellular membranes. MDR is efficiently generated with a relatively small fraction of membrane transporters. As the insertion of drugs into cellular membranes is widespread, there are no reasons why a drug should incorporate the membrane in the vicinity of a transporter. As a result a further elusive hypothesis is usually invoked: these transporters act like "vacuum cleaners" of drugs embedded in the membrane. Nonetheless, how these transporters attract drugs remains obscure. To clarify the "vacuum cleaner" notion, we suggest that during its residency time in cellular membranes, the lateral movement of drugs from their point of insertion to transporters is governed by Brownian's diffusion, which allows the drugs/transporters interaction. Taking into account the functionality of Pgp-like transporters, namely the extrusion of drugs from the plasma membrane inner leaflet, we characterize how the state of drug resistance is triggered involving: membrane endocytosis, drug physico-chemical properties and the surface density of Pgp-like transporters. In addition, the theory developed provides for the first time a theoretical proof of Lipinski's second rule with regard to drugs' size (or MW) selectivity on their permeation across cellular membranes.