Toxicological implications of hepatobiliary transporters.
Recent progress in molecular biological research has revealed that many types of transporters are expressed in the liver. Such xenobiotic transporters have a wide range of substrate specificity, which allows them to act as a barrier to protect the body from potentially harmful xenobiotics. Most of them mediate active transport of the substrates, leading to concentrative uptake and excretion into the hepatocytes and bile. Transport properties such as these may play a role in the toxicity of certain types of substrates. For example, anticancer agents such as methotrexate and irinotecan are efficiently excreted into the bile and such excretion has been suggested to account for their toxic gastrointestinal side-effects. A similar hypothesis has also been proposed for NSAIDs. Considering their tissue-specific expression, these transporters also appear to be a promising target for the delivery of small molecules, while simultaneously minimizing their side-effects. For example, transporters involved in the oral absorption, hepatic uptake, and biliary excretion of pravastatin, an HMG-CoA reductase inhibitor, ensure its enterohepatic circulation giving it an important pharmacokinetic advantage since its pharmacological target is the liver. Of the major ACE inhibitors currently available, temocaprilat is a substrate of hepatic transporters. Since the major elimination route for other ACE inhibitors is via urinary excretion, their plasma concentrations exhibit a high degree of inter-patient variability over a wide range of renal function whereas the concentrations of temocaprilat exhibit a much lower degree of inter-patient variability due to its elimination into the bile. Thus, the hepatobiliary transporters are involved in some aspects of toxicology and, therefore, a rational strategy for regulating the recognition by such transporters may be required for optimum drug design. This presentation will discuss the possible role of hepatic transporters from a toxicological point of view.
Kato
Yukio
Y
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ykato@p.kanazawa-u.ac.jp
Suzuki
Hiroshi
H
Sugiyama
Yuichi
Y
D000818:Animals; D001646:Bile / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004064:Digestive System / Q000187:drug effects; D004347:Drug Interactions; D006801:Humans; D008099:Liver / Q000378:metabolism*; D014116:Toxicology / Q000379:methods
D002352:Carrier Proteins