ReviewThe Complexities of Hepatic Drug Transport:Current Knowledge and Emerging ConceptsPriyamvada Chandra1and Kim L. R. Brouwer1,2Received November 21, 2003; accepted February 26, 2004Recently, hepatic transport processes have been recognized as important determinants of drug dispo-sition. Therefore, it is not surprising that characterization of the hepatic transport and biliary excretionproperties of potential drug candidates is an important part of the drug development process. Suchinformation also is useful in understanding alterations in the hepatobiliary disposition of compounds dueto drug interactions or disease states. Basolateral transport systems are responsible for translocatingmolecules across the sinusoidal membrane, whereas active canalicular transport systems are responsiblefor the biliary excretion of drugs and metabolites. Several transport proteins involved in basolateraltransport 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 andapical transport proteins in terms of substrate specificity, regulation by nuclear hormone receptors andintracellular signaling pathways, genetic differences, and role in drug interactions. Transport knockoutmodels and other systems available for hepatobiliary transport studies also are discussed. This overviewof hepatobiliary drug transport summarizes knowledge to date in this rapidly growing field and empha-sizes the importance of understanding these fundamental processes in hepatic drug disposition.KEY WORDS: ABC proteins; drug disposition; hepatic transport; hepatobiliary; SLC proteins; trans-porters.SIGNIFICANCE OF HEPATIC TRANSPORT SYSTEMSIN DRUG DISPOSITIONMany endogenous and exogenous compounds, includingdrugs, are eliminated from the body by the liver via metabo-lism and/or excretion. Though the metabolic aspects of he-patic clearance have been the focus of research for severaldecades, the important role of hepatic transport systems inthe hepatobiliary disposition of drugs and metabolites hasbeen recognized only recently. Lipophilic molecules maymove from plasma to hepatic cytosol by simple or facilitateddiffusion. However, numerous transport proteins are avail-able on the basolateral membrane of the hepatocyte to me-diate uptake of amphipathic and polar organic compounds, aswell as some lipophilic molecules, from sinusoidal plasma tohepatic cytosol. Hepatocellular protein binding and seques-tration may influence the hepatobiliary disposition of somecompounds. Hepatic transport proteins also play an impor-tant role in the excretion of drugs and metabolites from thehepatocyte. Uni- or bi-directional basolateral transport sys-tems translocate polar molecules from hepatic cytosol intoblood, whereas active canalicular transport systems are re-sponsible for the biliary excretion of drugs and metabolites.During the past decade, there has been a surge of interestin the field of drug transport, and knowledge regarding he-patic transport systems has grown substantially. There iswidespread interest in the hepatic transport of drugs and me-tabolites among pharmaceutical scientists, including medici-nal chemists, pharmacologists, and clinicians, for several rea-sons:1. Drug Design (Drug Delivery). Knowledge of struc-ture-transport relationships for hepatic transport proteinswould aid in the design of compounds with optimal transportproperties. In some cases, extensive hepatic uptake or en-hanced biliary excretion may be desirable characteristics for apotential drug candidate. In other situations, extensive he-patic uptake and biliary excretion may reduce systemic expo-sure and limit pharmacological activity, thus representing un-desirable properties of the molecule.2. Bioavailability. The liver is an important organ offirst-pass elimination. Reduced or erratic systemic availabilityof drugs after oral administration may be related to dietary,disease, or drug-induced alterations in hepatic transport sys-tems. For example, induction of a hepatic transport proteinresponsible for the hepatic uptake or biliary excretion of adrug could decrease systemic availability of that drug after1Division of Drug Delivery and Disposition, University of NorthCarolina at Chapel Hill, Chapel Hill, North Carolina 27599.2To whom correspondence should be addressed. (e-mail: [email protected])Pharmaceutical Research, Vol. 21, No. 5, May 2004 (© 2004)719 0724-8741/04/0500-0719/0 © 2004 Plenum Publishing Corporationoral administration. In addition to the liver, drug transportproteins that reside on the basolateral and apical membranesof the gastrointestinal epithelial cells also are crucial deter-minants of the bioavailability of many drug molecules.3. Biliary Excretion. Compounds are excreted into bileby ATP-dependent canalicular transport proteins. The extentto which most drugs and metabolites undergo biliary excre-tion in humans is not readily appreciated due to the difficul-ties inherent in directly accessing bile drainage in healthyindividuals. Many potentially useful therapeutic agents maybe excluded in the early stages of drug development due toextensive biliary excretion that limits systemic exposure. Bil-iary excretion of drugs or metabolites may expose the intes-tinal epithelia to pharmacologically active or toxic speciesthat can exert dose-limiting toxicities. Compounds excretedvia bile into the intestine may be reabsorbed into the systemiccirculation intact, metabolized with subsequent reabsorption,or may undergo elimination in the feces. Hepatic transportsystems are crucial determinants of the enterohepatic recy-cling of compounds.4. Interindividual Variability in Drug Pharmacokineticsand Pharmacodynamics. Disease-associated or genetic alter-ations in the expression and/or function of hepatic transportproteins may alter significantly the disposition of many en-dogenous and exogenous compounds, including drugs andmetabolites. Although this field of research is still in its in-fancy, hepatic transport systems clearly are responsible forimportant
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