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Membrane transporters in drug development

Nature Reviews Drug Discovery volume 9, pages 215–236 (2010)Cite this article

Subjects

Key Points

  • 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.

Abstract

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

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Figure 1: Selected human transport proteins for drugs and endogenous substances.
Figure 2: Decision tree for computer modelling of transporter proteins.

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Acknowledgements

This report is dedicated to the memory of John M. Strong (1937–2008), Deputy Director of the Laboratory of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA). J.M.S's insight and research career focused on understanding the determinants of drug–drug interactions, clinical pharmacology, drug-induced liver injury, and the translation of transporter biology to the drug safety evaluation paradigm. We are grateful for the able assistance of R. Bogenrief and C. Weiss in preparing this manuscript. We would like to acknowledge partial support from an National Institutes of Health grant, GM61390 and funds from the FDA Critical Path for the workshop leading to this report.

Author information

Authors and Affiliations

  1. K.M.G. is at the Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 513 Parnassus Avenue, California 94143-0912, USA. kathy.giacomini@ucsf.edu,

    Kathleen M. Giacomini

  2. S.-M.H. is at the Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993-0002, USA. ShiewMei.Huang@fda.hhs.gov,

    Shiew-Mei Huang

  3. D.J.T. is at Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, PO Box 368, Ridgefield, Connecticut 06877, USA. donald.tweedie@boehringer-ingelheim.com,

    Donald J. Tweedie

Consortia

The International Transporter Consortium

  • Kathleen M. Giacomini
  • , Shiew-Mei Huang
  • , Donald J. Tweedie
  • , Leslie Z. Benet
  • , Kim L.R. Brouwer
  • , Xiaoyan Chu
  • , Amber Dahlin
  • , Raymond Evers
  • , Volker Fischer
  • , Kathleen M. Hillgren
  • , Keith A. Hoffmaster
  • , Toshihisa Ishikawa
  • , Dietrich Keppler
  • , Richard B. Kim
  • , Caroline A. Lee
  • , Mikko Niemi
  • , Joseph W. Polli
  • , Yuicchi Sugiyama
  • , Peter W. Swaan
  • , Joseph A. Ware
  • , Stephen H. Wright
  • , Sook Wah Yee
  • , Maciej J. Zamek-Gliszczynski
  •  & Lei Zhang

Ethics declarations

Competing interests

Kim L. R. Brouwer is a co-inventor of sandwich cultured hepatocyte technology for quantification of biliary excretion (B-CLEAR), and is a co-founder and Chair of the Scientific Advisory Board for Qualyst, Inc., which has exclusively licensed this technology.

Peter W. Swaan receives funding from Eli Lilly & Co. to support postdoctoral scholars in his laboratory; he has stock in Xenoport, Inc. a company focused on developing chemical entities that utilize nutrient transporter mechanisms to improve the therapeutic benefits of drugs.

Xiaoyan Chu and Raymond Evers have no competing financial interests beyond employment by Merck Sharp and Dohme Corporation.

Volker Fischer has no competing financial interests beyond employment by Abbott Laboratories.

Kathleen M. Hillgren and Maciej J. Zamek-Gliszczynski have no competing financial interests beyond employment by Lilly Research Labs.

Caroline A. Lee has no competing financial interests beyond employment by Pfizer.

Joseph W. Polli has no competing financial interests beyond employment by GlaxoSmithKline.

Kathleen M. Giacomini, Shiew-Mei Huang, Donald J. Tweedie, Leslie Z. Benet, Amber Dahlin, Keith A. Hoffmaster, Toshihisa Ishikawa, Dietrich Keppler, Richard B. Kim, Mikko Niemi, Yuichi Sugiyama, Joseph A. Ware, Stephen H. Wright, Sook Wah Yee, and Lei Zhang declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

US FDA Guidance, Compliance and Regulatory Information — Clinical Pharmacology

US FDA Drug Development and Approval Processes — Drug Development and Drug Interactions

Glossary

Membrane transporters

Membrane-associated proteins that govern the transport of solutes (for example, drugs and other xenobiotics) into and out of cells. Transporters can play a vital role in determining drug concentrations in the systemic circulation and in cells. The two major superfamilies of membrane transporters are the ATP-binding cassette (ABC) and solute carrier (SLC) superfamilies.

Blood–brain barrier

The blood–brain barrier consists of endothelial cells connected by tight junctions. The endothelial cells, which are surrounded by astrocytes, separate the circulating blood and the brain interstitial space. The role of the blood–brain barrier is to protect the central nervous system by restricting and preventing the entry of toxic substances including drug molecules and bacteria into the brain. Included in this protective barrier are transporters such as P-glycoprotein.

Drug–drug interaction

(DDI). Concomitant administration of multiple drugs can result in altered levels of the drugs compared with administration of the drugs alone. DDI can result in higher (inhibition) or lower (induction) levels of the drug. For example, if drug A ('perpetrator' drug) inhibits a membrane transporter that drug B ('victim' drug) uses to enter into the cell, administration of drug A can lower the level of drug B in the cell and also potentially increase the level of drug B in the systemic circulation.

Drug-metabolizing enzymes

(DMEs). These are enzymes responsible for chemical modification of drugs usually to increase rate of elimination. The activity of these enzymes can be altered through inhibition or induction, thus affecting the rate of metabolism.

Pharmacokinetics

Pharmacokinetics describe what the body does to a drug. Pharmacokinetic parameters result from the absorption, distribution, metabolism and excretion properties of drugs, and provide information about the rates of elimination and systemic concentrations of drugs. The functional activity and level of a drug transporter can determine the amount of drug molecule transported into or out of specific tissues, which will determine the level of drugs in that tissue and also the systemic circulation.

Substrate or inhibitor

A substrate of a drug transporter is translocated across a membrane by the transporter. An inhibitor of a drug transporter can impair the uptake and/or efflux of another drug. Many inhibitors are not substrates, that is, they are not transported by the transporter. Substrates can competitively inhibit other substrates that interact at the same site(s) on the transporter.

Pharmacodynamics

Pharmacodynamics describe the extent and time course of the effects of drugs on physiological and pathophysiological processes. The relationship between drug concentration and drug effect is important in determining pharmacodynamics.

IC50

IC50 value, as used in this paper, is the concentration of an inhibitor needed to inhibit one-half of the transport rate of the substrate measured in the absence of the inhibitor. The IC50 of a drug is determined by a concentration–transport rate curve. To determine the IC50 value of an inhibitor of a drug transporter, the effect of increasing concentrations of the inhibitor on the transport rate of a substrate is determined.

Fraction unbound

(fu). This fraction represents the ratio of unbound drug concentration to total drug concentration in the plasma. The fu is determined by the affinity of drugs to the binding proteins (for example, albumin and α1-acid glycoprotein) in plasma and the total number of binding sites on the proteins.

Unbound inhibitor concentration

[I]. The unbound drug is the pharmacologically active species and is available for inhibition of transporters. Typically, mean unbound steady-state Cmax values following administration of the highest proposed clinical dose is used for [I]1 in the decision tree. Note that the definition of [I]1 used in this report differs from that described by Zhang et al. (Ref. 15) in the original published P-glycoprotein decision tree. Defining [I] as the unbound steady-state maximum concentration was intentionally done to provide consistency across the all the decision trees included in this report.

K i

Ki is the inhibition constant of the drug inhibitor, and for competitive inhibition is determined as, Ki = IC50/[1+([S]/Km)], in which [S] is the concentration of the drug substrate and Km is the affinity of the drug substrate for the drug transporter.

Absorption, distribution, metabolism and excretion

(ADME). The acronym ADME describes the factors that determine the overall exposure to an administered drug. Absorption describes uptake from the site of administration. Although usually referring to oral route, other routes can apply, for example, subcutaneous or buccal. As drug levels are typically measured systemically, oral absorption can be a function of movement across the mucosal surface of the intestinal tract, through the liver and into the systemic circulation via the vena cava. Distribution describes the extent of partitioning into tissues. Metabolism refers to a chemical change usually catalysed by enzymes such as the cytochrome P450s. The drug and its metabolites are excreted or eliminated usually by the kidney (in urine) or from the liver (via bile) or intestines into the faeces.

Drug clearance

The clearance of a drug is defined as the proportionality constant between rate of elimination and plasma concentration. The total clearance (CLTotal) reflects the rate of removal from the systemic circulation (the site of monitoring concentrations). Clearance by an organ can also be defined (for example, renal clearance (CLr) via excretion, and hepatic clearance (CLh) via metabolism and/or biliary excretion). Renal clearance of a drug is determined by glomerular filtration, and tubular secretion and reabsorption, both of which may be mediated by transporters.

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The International Transporter Consortium. Membrane transporters in drug development. Nat Rev Drug Discov 9, 215–236 (2010). https://doi.org/10.1038/nrd3028

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