Mechanisms of hepatic transport of drugs: implications for cholestatic drug reactions.
Hepatocellular and canalicular transport proteins are major determinants of the hepatic uptake and biliary excretion of xenobiotics and their metabolites. Recent advances in molecular cloning have resulted in the characterization of many of these transport systems. These advances have enabled the identification of a number of drugs that are substrates for the transporters, and it has facilitated studies of mechanisms of drug-induced cholestasis. This review summarizes the normal function of hepatobiliary transporters and their alteration by drugs or other foreign compounds. Although most of these investigations have been performed in animal models of drug-induced cholestasis, the application to human forms of drug-induced cholestasis is also discussed when possible. One important finding is that genetic polymorphisms can result in changes in drug transporter expression and function that could increase susceptibility to cholestatic drug reactions.
Bohan
Alan
A
Liver Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Boyer
James L
JL
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000494:pharmacology*; D002779:Cholestasis / Q000139:chemically induced*; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011110:Polymorphism, Genetic; D015262:Xenobiotics / Q000378:metabolism
D002352:Carrier Proteins; D004364:Pharmaceutical Preparations; D015262:Xenobiotics