Hepatobiliary Transport: Mechanisms, QSAR and Regulation

Over the last 5 years or so, there has been a significant increase in the molecular characterization of transport proteins in animals and man. This has led to a better understanding of the importance of such transport proteins in the disposition of endogenous compounds, drugs and other xenobiotics in many organs such as the intestine, liver, kidney and brain. The liver plays a key role in the clearance and excretion of many endogenous as well as xenobiotic substances and hepatobiliary excretion of drugs from blood, through the hepatocyte, and into the bile can be considered a three-step process; a) the uptake of drugs from blood into the hepatocyte through the sinusoidal (basolateral) membrane, b) transfer of drugs to metabolic sites and/or the biliary canalicular membrane inside the hepatocyte, c) excretion in to bile through the canalicular membrane. A wide variety of active transporters are known to be present at both the sinusoidal and the canalicular membrane to mediate the hepatobiliary transport. Many of the functionally predicted drug elimination systems in liver have now been cloned and characterized. A summary of the major hepatic sinusoidal and canalicular membrane transporters involved in transport of therapeutic drugs is provided in Fig. 1.