MDR2 P-GLYCOPROTEIN-MEDIATED LIPID SECRETION AND ITS RELEVANCE TO BILIARY DRUG TRANSPORT

Biliary excretion of xenobiotics is a complex process involving uptake into hepatocytes, internal sequestration and/or biotransformation, an d transport into bile. Phospholipid secretion was previously supposed to be a passive process in which the phospholipid was released into bi le by bile salt-induced extraction from the canalicular membrane by bi le salts. This idea needed adaptation when it was recognized that phos pholipid secretion not only depends on bile salt secretion but also re quires 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 can alicular membrane. This translocation will result in alterations in co mposition and/or arrangement of membrane lipids in such a way that pho spholipid can be extracted from the outer leaflet of the canalicular m embrane 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 informatio n to refine drug targeting protocols used for drugs that must exert th eir therapeutical effects in the biliary tree or intestinal tract.