Mechanism of multidrug resistance in relation to passive membrane permeation.

Passive uptake of drugs into cells is described in terms of the following steps: (1) massive immediate binding of the drugs to the outer leaflet of the plasma membrane resulting in practical equilibrium between extremely high drug concentrations at the cell surface compared to the drug concentration in the medium. (2) Due to their amphipathic nature, anticancer drugs are practically excluded from the lipid core of the membrane. They cross the lipid core by distinct flip-flop events that occur in the case of doxorubicin and daunorubicin after an average period of 0.7 and 0.15 min, respectively. (3) The drug reaching the inner leaflet of the plasma membrane is in practical equilibrium with the drug present in the cytoplasm. (4) Almost all the amounts of anticancer drugs present in the cells are bound by molecular sinks, such as DNA or cytoskeleton elements. The resistance afforded to multidrug resistant (MDR) cells by extrusion pumps, such as P-glycoprotein, is negatively correlated with the affinity of the drugs to the membranes and with their flip-flop rates across membranes. Binding rates of the drugs to membranes and intracellular sinks have no effect on drug concentration in the cytoplasm once equilibrium is reached between the passive uptake of drugs and their active extrusion.