CHAPTER 5. Drug Efflux Transporters: P-gp and BCRP

The efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) play important roles in protecting tissues from potentially harmful xenobiotic substances, mainly by virtue of their location in the intestinal epithelium and in the blood–brain barrier. As such they can limit both the absorption of orally administered drugs and their distribution to the central nervous system. Structural flexibility in the substrate binding sites of P-gp and BCRP enables them to transport a wide variety of compounds out of cells. Results of retrospective analyses indicate that a combination of physicochemical properties is important in determining rates of efflux of compounds. Medicinal chemistry design strategies for orally administered drugs may aim to minimize efflux [central nervous system (CNS) drugs] or to maximize it whilst maintaining adequate oral bioavailability (non-CNS drugs). Ranges of physicochemical parameters that are most likely to serve project objectives by mitigating or exploiting efflux are described, together with examples of design tactics successfully employed in drug discovery programmes which have targeted physicochemical parameters individually or in combination.