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UNC-Chapel Hill ENVR 442 - Study Guide

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Downloaded By: [University of North Carolina] At: 15:12 31 January 2008 Drug Metabolism Reviews, 39: 159–234, 2007Copyright © Informa HealthcareISSN: 0360-2532 print / 1097-9883 onlineDOI: 10.1080/03602530601093489159PRIMARY HEPATOCYTES: CURRENT UNDERSTANDING OF THE REGULATION OF METABOLIC ENZYMES AND TRANSPORTER PROTEINS, AND PHARMACEUTICAL PRACTICE FOR THE USE OF HEPATOCYTES IN METABOLISM, ENZYME INDUCTION, TRANSPORTER, CLEARANCE, AND HEPATOTOXICITY STUDIESNicola J. HewittScientific Writing Services, Wingertstrasse, Erzhausen, GermanyMaría José Gómez LechónUnidad de Hepatología Experimental, Centro de Investigación Hospital La Fe,Valencia, SpainJ. Brian Houston, David Hallifax, and Hayley S. BrownSchool of Pharmacy and Pharmaceutical Sciences, University of Manchester, UKPatrick MaurelINSERM, Montpellier, France; Univ Montpellier, Montpellier, FranceJ. Gerald KennaGlobal Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UKLena Gustavsson and Christina LohmannDiscovery DMPK & BA, AstraZeneca R&D Lund, SwedenChristian SkonbergDanish University of Pharmaceutical Sciences, Department of Pharmaceutics andAnalytical Chemistry, Universitetsparken, CopenhagenAndre GuillouzoINSERM Université de Rennes, FranceGregor TuschlDepartment of Molecular Toxicology, Institute of Toxicology, Merck KGaA,Frankfurterstrasse, Darmstadt, GermanyAlbert P. LiThe ADMET Group LLC, Rockville, MDEdward LeCluyseCellzDirect, Hillsboro Street, Pittsboro, NCAddress correspondence to Nicola J. Hewitt; E-mail: [email protected] By: [University of North Carolina] At: 15:12 31 January 2008 160 N. J. HEWITT ET AL.Geny M. M. GroothuisPharmacokinetics and Drug Delivery, University Centre for Pharmacy, Universityof Groningen, A.Deusinglaan, Groningen, The NetherlandsJan G. HengstlerCentre of Toxicology, Institute of Legal Medicine and Rudolf-Boehm Institute,Haertelstr, University of Leipzig, Leipzig, GermanyThis review brings you up-to-date with the hepatocyte research on: 1) in vitro–in vivocorrelations of metabolism and clearance; 2) CYP enzyme induction, regulation, and cross-talk using human hepatocytes and hepatocyte-like cell lines; 3) the function and regulationof hepatic transporters and models used to elucidate their role in drug clearance; 4) mecha-nisms and examples of idiosyncratic and intrinsic hepatotoxicity; and 5) alternative cell sys-tems to primary human hepatocytes. We also report pharmaceutical perspectives of thesetopics and compare methods and interpretations for the drug development process.INTRODUCTIONDrug metabolism and drug transport are major determinants of drug clearance,interindividual pharmacokinetic differences, clinical efficacy, and toxicity of drugs(Gomez-Lechón et al., 2003; Lu, 1998). Inappropriate pharmacokinetics can result ininadequate pharmacodynamic action and/or extremely wide variations in clinicalresponse. Unsatisfactory pharmacokinetic properties have been identified as a major rea-son for the failure of new chemical entities in drug development in man (Schuster et al.,2005). Moreover, hepatic metabolism of drugs as well as their interactions with hepatictransporters may cause toxicity (either to the liver itself or other organs) and contribute tovariability between individuals in susceptibility to such adverse drug reactions. Therefore,key issues in the early phase of drug discovery and development include not only anexhaustive characterization of pharmacological activity, but also investigation of meta-bolic stability, metabolite profiles, major metabolic routes involved in metabolite forma-tion, the enzymes involved, and the potential for enzyme inhibition or induction.Isolated hepatocytes are now recognized as one of the most relevant and practicalmodels with which the study of drug metabolism and transporter interactions is best per-formed. When isolated and handled appropriately, they contain a broad complement ofmetabolizing enzymes and transport proteins, organized in a physiologically relevant con-text and regulated via cellular processes that occur within the liver in vivo (e.g., nuclearhormone-mediated xenosensors). Microsomes continue to be the first-line screeningmodel for high throughput assays. However, studies undertaken with microsomes areincreasingly being replaced or complemented by the use of hepatocytes. The practical andtechnical difficulties posed by hepatocyte isolation have been largely circumvented by useof cryo-preserved cells. In fact, the number of publications in the last 5 years citing metab-olism in hepatocytes have increased by approximately 30%. During the same period, thenumber of citations of metabolism in microsomes dropped by 25% (source: MedLine).Microsomes are gradually being replaced by hepatocytes because the quality of cryo-preserved hepatocytes has improved. As a result of the increasing demand for a more rele-vant model, the application of hepatocytes to higher throughput assays has been improvedby more sophisticated automation instruments and miniaturization methods.Downloaded By: [University of North Carolina] At: 15:12 31 January 2008 HEPATOCYTE MODELS USED IN DRUG DEVELOPMENT 161This review focuses on the use of hepatocytes, as well as hepatocyte-like cell linesfor induction, metabolism, clearance, cytotoxicity, and transporter studies. Methodologiesused for each of these are outlined and interpretations of results are discussed. In vitro–in vivocorrelations are needed to demonstrate the predictive strength of any assay and are dis-cussed using selected case studies as examples.The Basic Hepatocyte Culture—does Matrix Overlay Make a Difference?The establishment of long-term cultures of primary hepatocytes has long been desiredand many efforts have been undertaken to achieve this goal (LeCluyse et al., 1996a,b). There isa strong need for robust long-term in vitro screening models, the use of which reduces thenumber of animals used in drug development. Today, cultures of primary human and animalhepatocytes have been adopted for a variety of pharmacological and toxicological experiments,allowing for the study of chronic effects in vitro. Although in vitro experimental models cannever resemble the complexity of a whole organism, their simplicity provides the ability to spe-cifically manipulate and analyze single parameters.Culturing hepatocytes in a sandwich configuration between two layers of gelledextracellular matrix proteins, with collagen I and matrigel being the most


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