D rug–drug interaction mediated by inhibition and induction of.pdfVIP

Advanced Drug Delivery Reviews 55 (2003) 53–81 /locate/drugdeliv D rug–drug interaction mediated by inhibition and induction of P-glycoprotein Jiunn H. Lin* Department of Drug Metabolism, Merck Research Laboratories, WP75A -203, West Point, PA 19486, USA Received 2 March 2002; accepted 28 June 2002 Abstract P-glycoprotein (P-gp), the most extensively studied ATP-binding cassette transporter, functions as a biological barrier by extruding toxic substances and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-gp plays a significant role in drug absorption and disposition. Like cytochrome P450 enzymes, inhibition and induction of P-gp have been reported as the causes of drug–drug interactions. Because many prototypic inhibitors and inducers affect both CYP3A4 and P-gp, many drug interactions caused by these inhibitors and inducers involve these two systems. Clinically, it is very difficult to quantitatively differentiate P-gp-mediated drug interactions versus CYP3A4-mediated drug interactions, unless their relative contributions can be accurately estimated. Therefore, care should be exercised when interpreting drug interaction data and exploring the underlying mechanisms of drug interactions.  2002 Elsevier Science B.V. All rights reserved. Keywords : P-glycoprotein-mediated drug interactions; Genetic polymorphism; Saturable efflux transport; Blood–brain barrier Con