chapter  8
76 Pages

The Role of P-Glycoprotein in Drug Disposition: Significance to Drug Development

The activity of transporters is now widely accepted as an important determinant of drug disposition. Certainly one major reason that transporters have become a key area of research that continues to grow involves the efflux pump, P-glycoprotein (P-gp). The transporter was initially discovered by Juliano and Ling as a transmembrane (TM) protein that was overexpressed in Chinese hamster ovary (CHO) cells treated with various chemotherapeutic agents that had become resistant to these cytotoxic drugs (1,2). In several cancerous tissues, overexpression of this protein is often associated with conferring the multidrug resistance (MDR)

phenotype that involves insensitivity to a variety of structurally unrelated cytotoxic compounds, some of which the MDR cell had not been previously exposed to. The " P " in P-gp stands for permeability, as this efflux transporter was found to reduce the permeability of a wide variety of chemically unrelated cell permeable substrates. Subsequent to the recognition of P-gp's role in cancer, P-gp was found to be expressed in many normal tissues, namely, epithelial and endothelial barrier tissues (3,4). In this capacity, P-gp provides a biochemical mechanism to modulate the trafficking of endogenous compounds and drugs across these barriers, and this activity has been shown to influence the disposition of these compounds. Since the recognition of its role in limiting the oral absorption of certain drugs (5-10), P-gp has emerged as an important determinant of the oral bioavailability of drug molecules. Additionally, P-gp is known to be a critical determinant of the distribution of its substrates, particularly to organs protected by blood-tissue barriers such as the central nervous system (CNS) (11,12). For certain substrates, P-gp has been shown to be a determinant of elimination, playing a role in renal and biliary excretion (13,14). Recently, it has been shown that P-gp efflux activity can have a profound influence on the extent of metabolism (15-18). In addition to influencing a substrate's disposition, it has recently been demonstrated that changes to P-gp efflux can cause clinically significant drug-drug interactions (DDIs) (19,20). These findings and many others have clearly demonstrated the importance of P-gp in disposition. For these reasons, the elucidation of P-gp's role in disposition continues to be a key scientific goal in drug discovery and development and in the further understanding of clinically used therapies that are substrates for this important efflux transporter.