Membrane transporters in drug development

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[1] University of California,K.M.G. is at the Department of Bioengineering and Therapeutic Sciences
[2] San Francisco,undefined
[3] 513 Parnassus Avenue,undefined
[4] California 94143-0912,undefined
[5] USA. kathy.giacomini@ucsf.edu,undefined
[6] S.-M.H. is at the Office of Clinical Pharmacology,undefined
[7] Office of Translational Sciences,undefined
[8] Center for Drug Evaluation and Research,undefined
[9] Food and Drug Administration,undefined
[10] 10903 New Hampshire Avenue,undefined
[11] Silver Spring,undefined
[12] Maryland 20993-0002,undefined
[13] USA. ShiewMei.Huang@fda.hhs.gov,undefined
[14] D.J.T. is at Boehringer Ingelheim Pharmaceuticals,undefined
[15] 900 Ridgebury Road,undefined
[16] PO Box 368,undefined
[17] Ridgefield,undefined
[18] Connecticut 06877,undefined
[19] USA. donald.tweedie@boehringer-ingelheim.com,undefined
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Membrane transporters are increasingly being recognized as important determinants of pharmacokinetics and have been found to play a role in the absorption and disposition of many drugs.In this report, the findings of the International Transporter Consortium (ITC), a group of individuals from academia, industry and regulatory agencies with expertise in membrane transporters, are presented. The goals of the ITC were to identify key transporters with a role in drug absorption and disposition; evaluate methodologies for characterization of drug transporter interactions; and develop criteria to inform the conduct of clinical drug–drug interaction (DDI) studies focused on transporters, which could be presented in the form of decision trees.The key transporters, P-glycoprotein (P-gp, ABCB1); breast cancer resistance protein (BCRP); organic anion transporters (OAT1 and OAT3); organic cation transporter (OCT2); and organic anion transporting polypeptides (OATP1B1 and OATP1B3), described in this report were selected based on evidence in the literature demonstrating that the transporters play a role in governing drug absorption and disposition and in mediating clinical DDIs.For each of the key transporters, substrate and inhibitors and methodologies for evaluating its function are described. The clinical significance of each transporter is discussed.An overview of the methods for studying drug interactions with transporters is presented including cell- and membrane-based systems, intact organs and in vivo models.A section on computational modelling algorithms using information from crystal structures and ligands is included to inform readers about the use of in silico methods to gain information about transporter–substrate interactions.A detailed discussion and suggested decision trees related to studying membrane transporters in drug development are described. The focus of the decision trees is on informing clinical DDI studies.
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页码:215 / 236
页数:21
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