The Complexities of Hepatic Drug Transport: Current Knowledge and Emerging Concepts |
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Authors: | Chandra Priyamvada Brouwer Kim L R |
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Institution: | Division of Drug Delivery and Disposition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. |
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Abstract: | Recently, hepatic transport processes have been recognized as important determinants of drug disposition. Therefore, it is not surprising that characterization of the hepatic transport and biliary excretion properties of potential drug candidates is an important part of the drug development process. Such information also is useful in understanding alterations in the hepatobiliary disposition of compounds due to drug interactions or disease states. Basolateral transport systems are responsible for translocating molecules across the sinusoidal membrane, whereas active canalicular transport systems are responsible for the biliary excretion of drugs and metabolites. Several transport proteins involved in basolateral transport have been identified including the Na(+)-taurocholate co-transporting polypeptide NTCP (SLC10A1)], organic anion transporting polypeptides OATPs (SLCO family)], multidrug resistance-associated proteins MRPs (ABCC family)], and organic anion and cation transporters OATs, OCTs (SLC22A family)]. Canalicular transport is mediated predominantly via P-glycoprotein (ABCB1), MRP2 (ABCC2), the bile salt export pump BSEP (ABCB11)], and the breast cancer resistance protein BCRP (ABCG2)]. This review summarizes current knowledge regarding these hepatic basolateral and apical transport proteins in terms of substrate specificity, regulation by nuclear hormone receptors and intracellular signaling pathways, genetic differences, and role in drug interactions. Transport knockout models and other systems available for hepatobiliary transport studies also are discussed. This overview of hepatobiliary drug transport summarizes knowledge to date in this rapidly growing field and emphasizes the importance of understanding these fundamental processes in hepatic drug disposition. |
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Keywords: | ABC proteins drug disposition hepatic transport hepatobiliary SLC proteins transporters |
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