Multiple recognition of various amphiphilic molecules by the multidrug resistance P-glycoprotein: molecular mechanisms and pharmacological consequences coming from functional interactions between various drugs.

P-glycoprotein (P-gp) is an active, ATP-dependent plasma membrane transporter which is responsible for the expulsion of various cytotoxic drugs with different chemical structures out of resistant (MDR) cells. It is also capable of transporting a number of other amphiphilic molecules, the so-called MDR-reversing agents, which belong to a very broad variety of chemical families. Moreover, P-gp can also play a role in steroid secretion and cellular detoxification by transporting various other substrates. In this review, we address the problem of the multiple recognition by P-gp of such a large number of amphiphilic molecules. This is both (i) from a basic viewpoint in order to discuss the underlying molecular mechanisms explaining how the general rule of substrate-enzyme specificity can be violated, and (ii) from a more applied pharmacological viewpoint to show in detail how the interaction of various drugs with P-gp leads to important consequences in terms of the relative effects of these drugs in the anticancer chemotherapy context, as well as for their pharmacokinetic distributions in the whole organism, rationalizing possible adverse drug reactions. In particular, we will present evidence that, independently of the technique used, the mutual interactions between P-gp transport substrates cannot always be reduced to simple competitive effects.