The drug efflux-metabolism alliance: biochemical aspects

The considerable overlap in the substrate selectivity and tissue localizati on of C-MA and P-glycoprotein has led to the hypothesis that this transport er and enzyme pair act as a coordinated absorption barrier against xenobiot ics. A historical perspective on the investigation of this interactive alli ance is given, starting from the understanding of the role of intestinal me tabolism in explaining cyclosporine clinical data. several animal studies u sing mdr1a(-/-) knockout mice have demonstrated P-glycoprotein's importance in limiting drug absorption and decreasing bioavailability. Human clinical studies investigating the importance of intestinal CYP3A and P-glycoprotei n through inhibition or induction of these proteins have provided further e vidence of this interaction. Recent in vitro studies using CYP3A4-expressin g Caco-2 cells are reported. These studies reveal that the role of P-glycop rotein in the intestine extends beyond simply limiting parent drug absorpti on but also includes increasing the access of drug to metabolism by CYP3A t hrough repeated cycles of absorption and efflux. (C) 2001 Elsevier Science BY All rights reserved.