P-glycoprotein or multidrug resistance protein (MDR1) is an adenosine triphosphate (ATP) binding cassette transporter (ABCB1) intensely investigated because it is an obstacle to successful pharmacotherapy of cancers. P-glycoprotein prevents cellular uptake of a large number of structurally and functionally diverse compounds, including most cancer therapeutics and in this way causes multidrug resistance (MDR). To overcome MDR, and thus improve cancer treatment, an understanding of P-glycoprotein inhibition at the molecular level is required. With this goal in mind, we propose rules that predict whether a compound is a modulator, substrate, inhibitor, or inducer of P-glycoprotein. This new set of rules is derived from a quantitative analysis of the drug binding and transport properties of P-glycoprotein. We further discuss the role of P-glycoprotein in immune surveillance and cell metabolism. Finally, the predictive power of the proposed rules is demonstrated with a set of FDA approved drugs which have been repurposed for cancer therapy.

Noncharged detergents are used as excipients in drug formulations. Until recently, they were considered as inert compounds, enhancing drug absorption essentially by improving drug solubility. However, many detergents insert into lipid membranes, although to different extents, and change the lateral packing density of membranes at high concentrations. Moreover, they bind to the efflux transporter P-glycoprotein (P-gp) and most likely to related transporters and metabolising enzymes with overlapping substrate specificities. If their affinity to P-gp is higher than that of the coadministered drug they act as modulators or inhibitors of P-gp and enhance drug absorption. Inhibition of P-gp and related proteins can, however, cause severe side effects. This paper first reviews the membrane binding propensity of different noncharged detergents (including poloxamers) and discusses their ability to bind to P-gp. Second, literature data on drug uptake enhancement by noncharged detergents, obtained in vivo and in vitro, are analysed at the molecular level. The present analysis provides the tools for an approximate and simple prior estimate of the membrane and P-gp binding ability of noncharged detergents based on a modular binding approach.

Modulators and inhibitors of multidrug efflux transporters, like P-glycoprotein, are used to reduce or inhibit multidrug resistance, MDR, which leads to a failure of the chemotherapy of e.g. cancers, epilepsy, bacterial, parasitic, and fungal diseases. Binding and transport of first-, second-, and third-generation modulators and inhibitors of P-glycoprotein are discussed, taking into account the properties of the drug (Hbonding potential, dimensions, and pKα values) as well as the properties of the membrane.