MDR2 P-glycoprotein-mediated lipid secretion and its relevance to biliary drug transport

Abstract Biliary excretion of xenobiotics is a complex process involving uptake into hepatocytes, internal sequestration and/or biotransformation, and transport into bile. Phospholipid secretion was previously supposed to be a passive process in which the phospholipid was released into bile by bile salt-induced extraction from the canalicular membrane by bile salts. This idea needed adaptation when it was recognized that phospholipid secretion not only depends on bile salt secretion but also requires the active participation of a protein, the mdr2 P-glycoprotein. In the current models mdr2 P-glycoprotein functions as a translocator of phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane. This translocation will result in alterations in composition and/or arrangement of membrane lipids in such a way that phospholipid can be extracted from the outer leaflet of the canalicular membrane by bile salts present in the canalicular lumen. Insight in the mechanisms of biliary phospholipid secretion could be useful for the development of strategies aimed at modifying the hepatic clearance of pharmaceuticals. Furthermore it could provide the necessary information to refine drug targeting protocols used for drugs that must exert their therapeutical effects in the biliary tree or intestinal tract.