eBriefing

The Portal Problem: Transporter Proteins and Drug Safety

The Portal Problem
Reported by
Alan Dove

Posted August 22, 2007

Overview

Transporter proteins play important roles in moving nutrients and toxins through different compartments of the body. But as pharmaceutical researchers have discovered, they are also involved in many surprising drug–drug interactions. An April 13, 2007, meeting of the Academy's Predictive Toxicology Discussion Group gathered academic and corporate researchers to discuss recent developments in the evolving field of transporter biology, as well as new guidelines from the U.S. Food and Drug Administration (FDA) that would require drug developers to test their compounds' effects on specific transporters.

Ellen Priest reviewed the transporters likely to be involved in drug metabolism, particularly ATP-binding cassette (ABC) transporters and active solute carrier (SLC) transporters, which have been shown to alter the metabolism of certain drugs. Keith Hoffmaster presented important insights into drug transport in the liver, and his group's discovery of a complex series of uptake and efflux pathways in the organ. Reina Bendayan presented studies showing that atazanavir, an antiretroviral drug used against HIV, boosts the expression of the efflux transporter P-glycoprotein (P-gp) at the blood–brain barrier; treating the cells with atazanavir and another protease inhibitor, ritonavir, also causes a twofold increase in the cells' expression of P-gp. Raymond Evers ended with a detailed analysis of the new FDA guidelines on transporter biology, and described efforts in his laboratory to identify potential drug–drug interactions early in the development pipeline.

Use the tabs above to find a meeting report and multimedia from this event.

Web Sites and Books

FDA Draft Guidance on Drug–Drug Interactions
This Web site provides drug developers with FDA's current understanding of how to conduct drug-interaction studies and resulting labeling.

UCSF Pharmacogenetics of Membrane Transporters
In this project, investigators from diverse disciplines are conducting a series of integrated studies to elucidate the pharmacogenetics of membrane transport proteins. This class of proteins is of great pharmacological importance as it provides the target for many commonly used prescription drugs and is a major determinant of the absorption, distribution, and elimination of many clinically used drugs.

Rowland M, Tozer TN. 1995. Clinical Pharmacokinetics: Concepts and Applications. Lippincott Williams & Wilkins, Philadelphia, PA.


Journal Articles

Introduction to Drug Transporters

Arrese M, Ananthanarayanan M. 2004. The bile salt export pump: molecular properties, function and regulation. Pflugers Arch. 449: 123-131.

Daniel H, Kottra G. 2004. The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pflugers Arch. 447: 610-618.

Fattinger K, Funk C, Pantze M, et al. 2001. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin. Pharmacol. Ther. 69: 223-231.

Hill G, Cihlar T, OO C, et al. 2002. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretioncorrelation of in vivo and in vitro studies. Drug Metab. Dispos. 30: 13-19. (PDF, 148 KB) Full Text

Kivisto KT, Grisk O, Hofmann U, et al. 2005. Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats. Drug Metab. Dispos. 33: 1593-1596. Full Text

Mwinyi J, Johne A, Bauer S, et al. 2004. Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clin. Pharmacol. Ther. 75: 415-421.

Polli JW, Jarrett JL, Studenberg SD, et al. 1999. Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm. Res. 16: 1206-1212.

Trauner M, Meier PJ, Boyer JL. 1998. Molecular pathogenesis of cholestasis. N. Engl. J. Med. 339: 1217-1227.

Van Herwaarden AE, Schimkel AH. 2006. The function of breast cancer resistance protein in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins. Trends Pharmacol. Sci. 27: 10-16.

Elucidating the Role of Drug Transporters in Hepatic Toxicity

Chen C, Pollack GM. 1998. Altered disposition and antinociception of [D-penicillamine(2,5)] enkephalin in mdr1a-gene-deficient mice. J. Pharmacol. Exp. Ther. 287: 545-552. Full Text

Chen C, Pollack GM. 1999. Enhanced antinociception of the model opioid peptide [D-penicillamine] enkephalin by P-glycoprotein modulation. Pharm. Res. 16: 296-301.

Daly AK, Aithal GP, Leathart JB, et al. 2006. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 132: 272-281.

Domansky K, Inman W, Serdy J, Griffith L. 2005. Perfused microreactors for liver tissue engineering. Conf. Proc. IEEE Eng. Med. Biol. Soc. 7: 7490-7492.

Funk C, Ponelle C, Scheuermann G, Pantze M. 2001. Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat. Mol. Pharmacol. 59: 627-635. Full Text

Hoffmaster KA, Zamek-Gliszczynski MJ, Pollack GM, Brouwer KL. 2004. Hepatobiliary disposition of the metabolically stable opioid peptide [D-Pen2, D-Pen5]-enkephalin (DPDPE): pharmacokinetic consequences of the interplay between multiple transport systems. J. Pharmacol. Exp. Ther. 311: 1203-1210. Full Text

Hoffmaster KA, Zamek-Gliszczynski MJ, Pollack GM, Brouwer KL. 2005. Multiple transport systems mediate the hepatic uptake and biliary excretion of the metabolically stable opioid peptide [D-penicillamine2,5]enkephalin. Drug Metab. Dispos. 33: 289-293. Full Text

Kostrubsky SE, Strom SC, Kalqutkar AS, et al. 2006. Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol. Sci. 90: 451-459. Full Text

Kubitz R, Saha N, Kuhlkamp T, et al. 2004. Ca2+-dependent protein kinase C isoforms induce cholestasis in rat liver. J. Biol. Chem. 279: 10323-10330. Full Text

Sivaraman A, Leach JK, Townsend S, et al. 2005. A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. Curr. Drug Metab. 6: 569-591.

Clinical Implications of Drug Transport in the Brain

Bendayan R, Lee G, Bendayan M. 2002. Functional expression and localization of P-glycoprotein at the blood brain barrier. Microsc. Res. Tech. 57: 365-380.

Bendayan R, Ronaldson PT, Gingras D, Bendayan M. 2006. In situ localization of P-glycoprotein (ABCB1) in human and rat brain. J. Histochem. Cytochem. 54: 1159-1167.

Dallas S, Miller DS and Bendayan R. 2006. Multidrug resistance-associated proteins (MRPs): expression and function in the central nervous system. Pharmacol. Rev. 58: 140-161.

Dallas S, Ronaldson PT, Bendayan M, Bendayan R. 2004. Multidrug resistance protein 1-mediated transport of saquinavir by microglia. NeuroReport 15: 1183-1186.

Dallas S, Zhu X, Baruchel S, et al. 2003. Functional expression of the multidrug resistance protein 1 in microglia. J. Pharmacol. Exp. Ther. 307: 282-290. Full Text

Garden GA. 2002. Microglia in human immunodeficiency virus-associated neurodegeneration. Glia 40: 240-251.

Hong M. Schlichter L, Bendayan R. 2000. A Na(+)-dependent nucleoside transporter in microglia. J. Pharmacol. Exp. Ther. 292: 366-374. Full Text

Lee G, Schlichter L, Bendayan M, Bendayan R. 2001. Functional expression of P-glycoprotein in rat brain microglia. J. Pharmacol. Exp. Ther. 299: 204-212. Full Text

Le Tiec C, Barrail A, Goujard C, Taburet AM. 2005. Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clin. Pharmacokinet. 44: 1035-1050.

McArthur JC, Haughey N, Gartner S, et al. 2003. Human immunodeficiency virus-associated dementia: an evolving disease. J. Neurovirol. 9: 205-221.

Ronaldson PT, Bendayan R. 2006. HIV-1 viral envelope glycoprotein gp120 triggers an inflammatory response in cultured rat astrocytes and regulates the functional expression of P-glycoprotein. Mol. Pharmacol. 70: 1087-1098.

Ronaldson PT, Bendayan M, Gingras D, et al. 2004. Cellular localization and functional expression of P-glycoprotein in rat astrocyte cultures. J. Neurochem. 89: 788-800. Full Text

Ronaldson PT, Lee G, Dallas S, Bendayan R. 2004. Involvement of P-glycoprotein in the transport of saquinavir and indinavir in rat brain microvessel endothelial and microglia cell lines. Pharm. Res. 21: 811-818.

Sawchuk RJ, Yang Z. 1999. Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system. Adv. Drug Del. Rev. 39: 5-31.

Yazdanian M. 1999. Blood–brain barrier properties of human immunodeficiency virus antiretrovirals. J. Pharm. Sci. 88: 950-954.

MDR1 P-glycoprotein and Beyond

Bleasby K, Castle JC, Roberts CJ, et al. 2006. Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition. Xenobiotica 36: 963-968.

Chu XY, Bleasby K, Yabut J, et al. 2007. Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J. Pharmacol. Exp. Ther. 321: 673-683.

Fromm MF. 2004. Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol. Sci. 25: 423-429.

Huang SM, Temple R, Throckmorton DC, Lesko LJ. 2007. Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin. Pharmacol. Ther. 81: 298-304.

Keogh JP, Kunta JR. 2006. Development, validation and utility of an in vitro technique for assessment of potential clinical drug–drug interactions involving P-glycoprotein. Eur. J. Pharm. Sci. 27: 453-554.

Mahar Doan KM, Humphreys JE, Webster LO, et al. 2002. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J. Pharmacol. Exp. Ther. 303: 1029–1037. Full Text

Polli JW, Wring SA, Humphreys JE, et al. 2001. Rational use of in vitro P-glycoprotein assays in drug discovery. J. Pharmacol. Exp. Ther. 299: 620-628. Full Text

Takeuchi T, Yoshitomi S, Higuchi T, et al. 2006. Establishment and characterization of the transformants stably-expressing MDR1 derived from various animal species in LLC-PK1. Pharm. Res. 23 1460-1472.

Wang Q, Rager JD, Weinstein K, et al. 2005. Evaluation of the MDR-MDCK cell line as a permeability screen for the blood–brain barrier. Int. J. Pharm. 288: 349-359.

Yamazaki M, Neway WE, Ohe T, et al. 2001. In vitro substrate identification studies for P-glycoprotein-mediated transport: species difference and predictability of in vivo results. J. Pharmacol. Exp. Ther. 296: 723-735. Full Text

Speakers

Ellen Priest, PhD

Hoffmann-LaRoche
e-mail

Ellen Priest is a principal scientist in the Drug Metabolism group of the Nonclinical Drug Safety department at Hoffmann-LaRoche in Nutley, NJ. Priest completed her graduate work at Georgetown University. After earning her doctorate under the direction of Paul Roepe, she joined Roche as a research associate. Her primary focus is on predicting drug transporter-mediated drug–drug interactions, using in vitro methods.

Keith Hoffmaster, PhD

Pfizer Research Technology Center
e-mail | publications

Keith Hoffmaster is a principal scientist at the Pfizer Research Technology Center in Cambridge, MA. He received his PhD in drug delivery and disposition from the University of North Carolina at Chapel Hill. At Pfizer, his current research focus is on developing and evaluating innovative technologies to improve predictions of hepatic clearance, understanding the risks of transporter-mediated drug interactions in the liver, and assessing the potential for hepatotoxicity of new chemical entities.

Hoffmaster was appointed as a visiting scientist at the Massachusetts Institute of Technology in 2005, and he is an active member of the American Association of Pharmaceutical Scientists (AAPS). He was recently elected co-chair of the AAPS's Drug Transport Focus Group for 2007 and 2008. An author on more than 40 publications and presentations on drug absorption, deposition, metabolism, excretion, and toxicology, he has also lectured on these topics on several occasions at leading academic graduate programs.

Reina Bendayan, PharmD

University of Toronto
e-mail | web site | publications

Reina Bendayan is an associate professor and chair of the Graduate Department of Pharmaceutical Sciences, in the Leslie Dan Faculty of Pharmacy at the University of Toronto. After obtaining a bachelor's degree in pharmacy and completing a hospital pharmacy residency at the University of Montreal, Bendayan moved to the University of Florida for her doctorate of pharmacy. She then returned to the north for a three-year Medical Research Council postdoctoral fellowship program in clinical pharmacy and membrane cell biology at the University of Toronto.

Bendayan's research program focuses primarily on membrane transport and therapeutics, with an emphasis on HIV/AIDS antiviral drug transport and metabolism in the brain. Her research is funded primarily by the Canadian Institute of Health Research, the Canadian Foundation for AIDS Research, and the Ontario HIV Treatment Network of the Ministry of Health of Ontario.

Raymond Evers, PhD

Merck & Co.
e-mail | publications

Raymond Evers studied biology at the University of Amsterdam, where he also earned his PhD based on work performed at the Max Planck Institute for Biology in Tübingen, Germany. He did his postdoctoral work at the German Cancer Research Center in Heidelberg, and the Netherlands Cancer Institute in Amsterdam. Currently, he is working as an associate director in the Department of Drug Metabolism at Merck and Company in Rahway, NJ, where he oversees an in vitro technology group. His responsibilities include studying the propensity of drug candidates to cause pharmacokinetic drug–drug interactions due to enzyme inhibition or activation of nuclear receptors, and investigating the role of transporters in drug absorption, disposition, and drug–drug interactions.


Alan Dove

Alan Dove is a science writer and reporter for Nature Medicine, Nature Biotechnology, and Bioscience Technology. He also teaches at the NYU School of Journalism, and blogs at http://dovdox.com.