Challenges with the precise prediction of ABC-transporter interactions for improved drug discovery

References

• Estudante M, Morais JG, Siveral G, et al. Intestinal drug transporters: an overview. Adv Drug Deliv Rev. 2013;65:1340–1356.
   PubMed Web of Science ®Google Scholar
• Köck K, Brouwer KLR. A perspective on efflux transport proteins in the liver. Clin Pharmacol Ther. 2012;92:599–612.
   PubMed Web of Science ®Google Scholar
• Morrissy KM, Stocker SL, Witter MB, et al. Renal transporters in drug development. Annu Rev Pharmacol Toxicol. 2013;53:503–529.
   PubMed Web of Science ®Google Scholar
• Mahringer A, Fricker G. ABC transporters at the blood-brain barrier. Expert Opin Drug Metab Toxicol. 2016;12:499–508.
   PubMed Web of Science ®Google Scholar
• Lee SC, Arya V, Yang X, et al. Evaluation of transporters in drug development: current status and contemporary issues. Adv Drug Deliv Rev. 2017;116:100–118.
   PubMed Web of Science ®Google Scholar
• Ellens H, Johnson M, Lawrence SK, et al. Prediction of the transporter-mediated drug-drug interaction potential of dabrafenib and its major circulating metabolites. Drug Metab Dispos. 2017;45:646–656.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Han YH, Putluru SP, et al. Diclofenac and its acyl glucuronide: determination of in vivo exposure in human subjects and characterization as human drug transporter substrates in vitro. Drug Metab Dispos. 2016;44:320–328.
   PubMed Web of Science ®Google Scholar
• Nagasaka Y, Oda K, Iwatsubo T, et al. Effects of aripiprazole and its active metabolite dehydroaripiprazole on the activities of drug efflux transporters expressed both in the intestine and at the blood-brain barrier. Biopharm Drug Dispos. 2012;33:304–315.
   PubMed Web of Science ®Google Scholar
• Weiss J, Kocher J, Mueller C, et al. Impact of enzalutamide and its main metabolite N-desmethyl enzalutamide on pharmacokinetically important drug metabolizing enzymes and drug transporters. Biopharm Drug Dispos. 2017;38:517–525.
   PubMed Web of Science ®Google Scholar
• Bikadi Z, Hazai I, Malik D, et al. Predicting P-glycoprotein-mediated drug transport based on support vector machine and three-dimensional crystal structure of P-glycoprotein. PLoS One. 2011;6:e25815.
   PubMed Web of Science ®Google Scholar
• Chen L, Li Y, Yu H, et al. Computational models for predicting substrates or inhibitors of P-glycoprotein. Drug Discov Today. 2012;17:343–351.
   PubMed Web of Science ®Google Scholar
• Ecker GF, Stockner T, Chiba P. Computational models for prediction of interactions with ABC-transporters. Drug Discov Today. 2008;13:311–317.
   PubMed Web of Science ®Google Scholar
• Taylor NMI, Manolaridis I, Jackson SM, et al. Structure of the human multidrug transporter ABCG2. Nature. 2017;546:504–509.
   PubMed Web of Science ®Google Scholar
• Kim Y, Chen J. Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science. 2018;359:915–919.
   PubMed Web of Science ®Google Scholar
• Desai PV, Sawada GA, Watson IA, et al. Integration of in silico and in vitro tools for scaffold optimization during drug discovery: predicting P-glycoprotein efflux. Mol Pharm. 2013;10:1249–1261.
   PubMed Web of Science ®Google Scholar
• Chen L, Li Y, Zhao Q, et al. ADME evaluation in drug discovery. 10. Predictions of P-glycoprotein inhibitors using recursive partitioning and naive Bayesian classification techniques. Mol Pharm. 2011;8(3):889–900.
   PubMed Web of Science ®Google Scholar
• Chang C, Bahadduri PM, Polli JE, et al. Rapid identification of P-glycoprotein substrates and inhibitors. Drug Metab Dispos. 2006;34(12):1976–1984.
   PubMed Web of Science ®Google Scholar
• Broccatelli F, Carosati E, Neri A, et al. A novel approach for predicting P-glycoprotein (ABCB1) inhibition using molecular interaction fields. J Med Chem. 2011;54(6):1740–1751.
   PubMed Web of Science ®Google Scholar
• Sun H. A naive Bayes classifier for prediction of multidrug resistance reversal activity on the basis of atom typing. J Med Chem. 2005;48(12):4031–4039.
   PubMed Web of Science ®Google Scholar
• Sim HM, Loh KY, Yeo WK, et al. Aurones as modulators of ABCG2 and ABCB1: synthesis and structure-activity relationships. ChemMedChem. 2011;6(4):713–724.
   PubMed Web of Science ®Google Scholar
• Wei Y, Ma Y, Zhao Q, et al. New use for an old drug: inhibiting ABCG2 with sorafenib. Mol Cancer Ther. 2012;11(8):1693–1702.
   PubMed Web of Science ®Google Scholar
• Pan Y, Chothe PP, Swaan PW. Identification of novel breast cancer resistance protein (BCRP) inhibitors by virtual screening. Mol Pharm. 2013;10(4):1236–1248.
   PubMed Web of Science ®Google Scholar
• Matsson P, Englund G, Ahlin G, et al. A global drug inhibition pattern for the human ATP-binding cassette transporter breast cancer resistance protein (ABCG2). J Pharmacol Exp Ther. 2007;323:19–30.
   PubMed Web of Science ®Google Scholar
• Cramer J, Kopp S, Bates SE, et al. Multispecificity of drug transporters: probing inhibitor selectivity for the human drug efflux transporters ABCB1 and ABCG2. ChemMedChem. 2007;2(12):1783–1788.
   PubMed Web of Science ®Google Scholar
• Giri N, Agarwal S, Shaik N, et al. Substrate-dependent breast cancer resistance protein (Bcrp1/Abcg2)-mediated interactions: consideration of multiple binding sites in in vitro assay design. Drug Metab Dispos. 2009;37:560–570.
   PubMed Web of Science ®Google Scholar
• Sáfár Z, Vaskó B, Ritchie TK, et al. Investigating ABCB1-mediated drug-drug interactions: considerations for in vitro and in vivo assay design. Curr Drug Metab. 2016;17(5):430–455.
   PubMed Web of Science ®Google Scholar
• Zolnerciks JK, Booth-Genthe CL, Gupta A, et al. Substrate- and species-dependent inhibition of P-glycoprotein-mediated transport: implications for predicting in vivo drug interactions. J Pharm Sci. 2011;100:3055–3061.
   PubMed Web of Science ®Google Scholar
• Galetin A, Zhao P, Huang SM. Physiologically based pharmacokinetic modeling of drug transporters to facilitate individualized dose prediction. J Pharm Sci. 2017;106:2204–2208.
   PubMed Web of Science ®Google Scholar
• Poggesi I, Snoeys J, Van Peer A. The successes and failures of physiologically based pharmacokinetic modeling: there is room for improvement. Expert Opin Drug Metab Toxicol. 2014;10:631–635.
   PubMed Web of Science ®Google Scholar
• Espie P, Tytgat D, Sargentini-Maier ML, et al. Physiologically based pharmacokinetics (PBPK). Drug Metab Rev. 2009;41:391–407.
   PubMed Web of Science ®Google Scholar
• Pan Y, Hsu V, Grimstein M, et al. The application of physiologically based pharmacokinetic modeling to predict the role of drug transporters: scientific and regulatory perspectives. J Clin Pharmacol. 2016;56(suppl 7):S122–S131.
   PubMedGoogle Scholar
• Brouwer KL, Keppler D, Hoffmaster KA, et al. In vitro methods to support transporter evaluation in drug discovery and development. Clin Pharmacol Ther. 2013;94:95–112.
   PubMed Web of Science ®Google Scholar
• Volpe DA. Transporter assays as useful in vitro tools in drug discovery and development. Expert Opin Drug Discov. 2016;11:91–103.
   PubMed Web of Science ®Google Scholar
• Zamek-Gliszczynski MJ, Lee CA, Poirier A, et al. ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans. Clin Pharmacol Ther. 2013;94:64–79.
   PubMed Web of Science ®Google Scholar
• Glavinas H, von Richter O, Vojnits K, et al. Calcein assay: a high-throughput method to assess P-gp inhibition. Xenobiotica. 2011;41:712–719.
   PubMed Web of Science ®Google Scholar
• Jouan E, Le Vée M, Mayati A, et al. Evaluation of P-glycoprotein inhibitory potential using a Rhodamine 123 accumulation assay. Pharmaceutics. 2016;8:E12.
   PubMed Web of Science ®Google Scholar
• Burkina V, Rasmussen MK, Pilipenko N, et al. Comparison of xenobiotic-metabolising human, porcine, rodent, and piscine cytochrome P450. Toxicology. 2017;375:10–27.
   PubMed Web of Science ®Google Scholar
• Nishimuta H, Nakagawa T, Nomura N, et al. Species differences in hepatic and intestinal metabolic activities for 43 human cytochrome P450 substrates between humans and rats or dogs. Xenobiotica. 2013;43:948–955.
   PubMed Web of Science ®Google Scholar
• Collett A, Tanianis-Hughes J, Hallifax D, et al. P-glycoprotein effects on oral absorption: correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo. Pharm Res. 2004;21:819–826.
   PubMed Web of Science ®Google Scholar
• Karibe T, Hagihara-Nakagomi R, Abe K, et al. Evaluation of the usefulness of breast cancer resistance protein (BCRP) knockout mice and BCRP inhibitor-treated monkeys to estimate the clinical impact of BCRP modulation on the pharmacokinetics of BCRP substrates. Pharm Res. 2015;32:1634–1647.
   PubMed Web of Science ®Google Scholar
• Nakanishi H, Yonezawa A, Matsubara K, et al. Impact of P-glycoprotein and breast cancer resistance protein on the brain distribution of antiepileptic drugs in knockout mouse models. Eur J Pharmacol. 2013;710:20–28.
   PubMed Web of Science ®Google Scholar
• Scheer N, Balimane P, Hayward MD, et al. Generation and characterization of a novel multidrug resistance protein 2 humanized mouse line. Drug Metab Dispos. 2012;40:2212–2218.
   PubMed Web of Science ®Google Scholar
• Zamek-Gliszczynski MJ, Bedwell DW, Bao JQ, et al. Characterization of SAGE Mdr1a (P-gp), Bcrp, and Mrp2 knockout rats using loperamide, paclitaxel, sulfasalazine, and carboxydichlorofluorescein pharmacokinetics. Drug Metab Dispos. 2012;40:1825–1833.
   PubMed Web of Science ®Google Scholar
• Sadiq MW, Uchida Y, Hoshi Y, et al. Validation of a P-glycoprotein (P-gp) humanized mouse model by integrating selective absolute quantification of human MDR1, Mouse Mdr1a and Mdr1b protein expressions with in vivo functional analysis for blood-brain barrier transport. PLoS One. 2015;10(5):e0118638.
   PubMed Web of Science ®Google Scholar
• Dallas S, Salphati L, Gomez-Zepeda D, et al. Generation and characterization of a breast cancer resistance protein humanized mouse model. Mol Pharmacol. 2016;89:492–504.
   PubMed Web of Science ®Google Scholar
• Scheer N, Wolf CR. Genetically humanized mouse models of drug metabolizing enzymes and transporters and their applications. Xenobiotica. 2014;44:96–108.
   PubMed Web of Science ®Google Scholar
• Jaiswal S, Sharma A, Shukla M, et al. Novel pre-clinical methodologies for pharmacokinetic drug-drug interaction studies: spotlight on “humanized” animal models. Drug Metab Rev. 2014;46:475–493.
   PubMed Web of Science ®Google Scholar
• Chu X, Bleasby K, Evers R. Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin Drug Metab Toxicol. 2013;9:237–252.
   PubMed Web of Science ®Google Scholar
• Bhoopathy S, Bode C, Naageshwaran V, et al. Principles and experimental considerations for in vitro transporter interaction assays. Methods Mol Biol. 2014;1113:229–252.
   PubMedGoogle Scholar
• Matsson P, Pedersen JM, Norinder U, et al. Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs. Pharm Res. 2009;26:1816–1831.
   PubMed Web of Science ®Google Scholar
• Pedersen JM, Khan EK, Cas B, et al. Substrate and method dependent inhibition of three ABC-transporters (MDR1, BCRP, and MRP2). Eur J Pharm Sci. 2017;103:70–76.
   PubMed Web of Science ®Google Scholar
• Poirier A, Portmann R, Cascais AC, et al. The need for human breast cancer resistance protein substrate and inhibition evaluation in drug discovery and development: why, when, and how? Drug Metab Dispos. 2014;42:1466–1477.
   PubMed Web of Science ®Google Scholar
• Suzuyama N, Katoh M, Takeuchi T, et al. Species differences of inhibitory effects on P-glycoprotein-mediated drug transport. J Pharm Sci. 2007;96:1609–1618.
   PubMed Web of Science ®Google Scholar
• Wang Q, Strab R, Kardos P, et al. Application and limitation of inhibitors in drug-transporter interactions studies. Int J Pharm. 2008;356:12–18.
   PubMedGoogle Scholar
• Mease K, Sane R, Podila L, et al. Differential selectivity of efflux transporter inhibitors in Caco-2 and MDCK-MDR1 monolayers: a strategy to assess the interaction of a new chemical entity with P-gp, BCRP, and MRP2. J Pharm Sci. 2012;101:1888–1897.
   PubMed Web of Science ®Google Scholar
• Tang F, Horie K, Borchardt RT. Are MDCK cells transfected with the human MDR1 gene a good model of the human intestinal mucosa?. Pharm Res. 2002;19:765–772.
   PubMed Web of Science ®Google Scholar
• Tang F, Horie K, Borchardt RT. Are MDCK cells transfected with the human MRP2 gene a good model of the human intestinal mucosa?. Pharm Res. 2002;19:773–779.
   PubMed Web of Science ®Google Scholar
• Aller SG, Yu J, Ward A, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 2009;323:1718–1722.
   PubMed Web of Science ®Google Scholar
• Martinez L, Arnaud O, Henin E, et al. Understanding polyspecificity within the substrate-binding cavity of the human multidrug resistance P-glycoprotein. FEBS J. 2014;281:673–682.
   PubMed Web of Science ®Google Scholar
• Ekins S, Kim RB, Leake BF, et al. Three-dimensional quantitative structure-activity relationships of P-glycoprotein inhibitors and substrates. Mol Pharmacol. 2002;61:974–981.
   PubMed Web of Science ®Google Scholar
• Bocci G, Moreau A, Vayer P, et al. New insights in the in vitro characterisation and molecular modelling of the P-glycoprotein inhibitory promiscuity. Eur J Pharm Sci. 2018;121:85–94.
   PubMed Web of Science ®Google Scholar
• Bentz J, O’Connor MP, Bednarczyk D, et al. Variability in P-glycoprotein inhibitory potency (IC50) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria. Drug Metab Dispos. 2013;41:1347–1366.
   PubMed Web of Science ®Google Scholar
• Bleasby K, Castle JC, Roberts CJ, et al. Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition. Xenobiotica. 2006;36:963–988.
   PubMed Web of Science ®Google Scholar
• Atilano-Roque A, Roda G, Fogueri U, et al. Effect of disease pathologies on transporter expression and function. J Clin Pharmacol. 2016;56(Suppl 7):S205–S221.
   PubMedGoogle Scholar
• Shirasaka Y, Sakane T, Yamashita S. Effect of P-glycoprotein expression levels on the concentration-dependent permeability of drugs to the cell membrane. J Pharm Sci. 2008;97:553–565.
   PubMed Web of Science ®Google Scholar
• Harwood MD, Achour B, Neuhoff S, et al. In vitro-in vivo extrapolation scaling factors for intestinal P-glycoprotein and breast cancer resistance protein: part II. The impact of cross-laboratory variations of intestinal transporter relative expression factors on predicted drug disposition. Drug Metab Dispos. 2016;44:476–480.
   PubMed Web of Science ®Google Scholar
• Wang L, Prasad B, Salphati L, et al. Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics. Drug Metab Dispos. 2015;43:367–374.
   PubMed Web of Science ®Google Scholar
• Prasad B, Lai Y, Lin Y, et al. Interindividual variability in the hepatic expression of the human breast cancer resistance protein (BCRP/ABCG2): effect of age, sex, and genotype. J Pharm Sci. 2013;102:787–793.
   PubMed Web of Science ®Google Scholar
• Prasad B, Evers R, Gupta A, et al. Interindividual variability in hepatic organic anion-transporting polypeptides and P-glycoprotein (ABCB1) protein expression: quantification by liquid chromatography tandem mass spectroscopy and influence of genotype, age, and sex. Drug Metab Dispos. 2014;42:78–88.
   PubMed Web of Science ®Google Scholar
• Deo AK, Prasad B, Balogh L, et al. Interindividual variability in hepatic expression of the multidrug resistance-associated protein 2 (MRP2/ABCC2): quantification by liquid chromatography/tandem mass spectrometry. Drug Metab Dispos. 2012;40:852–855.
   PubMed Web of Science ®Google Scholar
• Meier Y, Pauli-Magnus C, Zanger UM, et al. Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology. 2006;44:62–74.
   PubMed Web of Science ®Google Scholar
• Li M, Yuan H, Li N, et al. Identification of interspecies difference in efflux transporters of hepatocytes from dog, rat, monkey and human. Eur J Pharm Sci. 2008;35:114–126.
   PubMed Web of Science ®Google Scholar
• Katoh M, Suzuyama N, Takeuchi T, et al. Kinetic analyses for species differences in P-glycoprotein-mediated drug transport. J Pharm Sci. 2006;95:2673–2683.
   PubMed Web of Science ®Google Scholar
• Zimmermann C, Van de Wetering K, Van de Steeg E, et al. Species-dependent transport and modulation properties of human and mouse multidrug resistance protein 2 (MRP2/Mrp2, ABCC2/Abcc2). Drug Metab Dispos. 2008;36:631–640.
   PubMed Web of Science ®Google Scholar
• Lee CA, Cook JA, Reyner EL, et al. P-glycoprotein related drug interactions: clinical importance and a consideration of disease states. Expert Opin Drug Metab Toxicol. 2010;6:603–619.
   PubMed Web of Science ®Google Scholar
• Chu X, Korzekwa K, Elsby R, et al. Intracellular drug concentrations and transporters: measurement, modeling, and implications for the liver. Clin Pharmacol Ther. 2013;94:126–141.
   PubMed Web of Science ®Google Scholar
• Smith DA, Di L, Kerns EH. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov. 2010;9:929–939.
   PubMed Web of Science ®Google Scholar
• Zhou F, Zhang J, Li P, et al. Toward a new age of cellular pharmacokinetics in drug discovery. Drug Metab Rev. 2011;43:335–345.
   PubMed Web of Science ®Google Scholar
• Mateus A, Treyer A, Wegler C, et al. Intracellular drug bioavailability: a new predictor of system dependent drug disposition. Sci Rep. 2017;7:43047.
   PubMed Web of Science ®Google Scholar
• Volpe DA, Hamed SS, Zhang LK. Use of different parameters and equations for calculation of IC50 values in efflux assays: potential sources of variability in IC50 determination. AAPS J. 2014;16:172–180.
   PubMed Web of Science ®Google Scholar
• Balimane PV, Marino A, Chong S. P-gp inhibition potential in cell-based models: which “calculation” method is the most accurate? AAPS J. 2008;10:577–586.
   PubMedGoogle Scholar
• Sugimoto H, Matsumoto S, Tachibana M, et al. Establishment of in vitro P-glycoprotein inhibition assay and its exclusion criteria to assess the risk of drug-drug interaction at the drug discovery stage. J Pharm Sci. 2011;100:4013–4023.
   PubMed Web of Science ®Google Scholar
• Cook JA, Feng B, Fenner KS, et al. Refining the in vitro and in vivo critical parameters for P-glycoprotein, [I]/IC50 and [I2]/IC50, that allow for the exclusion of drug candidates from clinical digoxin interaction studies. Mol Pharm. 2010;7(2):398–411.
   PubMed Web of Science ®Google Scholar
• Kishimoto W, Ishiguro N, Ludwig-Schwellinger E, et al. Usefulness of a model-based approach for estimating in vitro P-glycoprotein inhibition potency in a transcellular transport assay. J Pharm Sci. 2016;105:891–896.
   PubMed Web of Science ®Google Scholar
• Fenner KS, Troutman MD, Kempshall S, et al. Drug-drug interactions mediated through P-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug. Clin Pharmacol Ther. 2009;85:173–181.
   PubMed Web of Science ®Google Scholar
• Ellens H, Deng S, Coleman J, et al. Application of receiver operating characteristic analysis to refine the prediction of potential digoxin drug interactions. Drug Metab Dispos. 2013;41:1367–1374.
   PubMed Web of Science ®Google Scholar
• Agarwal S, Arya V, Zhang L. Review of P-gp inhibition data in recently approved new drug applications: utility of the proposed [I1]/IC50 and [I2]/IC50 criteria in the P-gp decision tree. J Clin Pharmacol. 2013;53:228–233.
   PubMed Web of Science ®Google Scholar
• Arya V, Vaidyanathan J, Zhou T, et al. Statistical analysis to compare various in vitro criteria for predicting P-glycoprotein transporter mediated drug-drug interactions in vivo. Clin Pharmacol Ther. 2017;101(S1):S21.
   Web of Science ®Google Scholar
• Poirier A, Cascais AC, Bader U, et al. Calibration of in vitro multidrug resistance protein 1 substrate and inhibition assays as a basis to support the prediction of clinically relevant interactions in vivo. Drug Metab Dispos. 2014a;42:1411–1422.
   PubMed Web of Science ®Google Scholar
• Food and Drug Administration. In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies. Guidance for Industry. 2017. [cited 2018 Feb 2]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM581965.pdf
   Google Scholar
• European Medicinal Agency. Guideline on the investigation of drug interactions. 2012. [cited 2018 Feb 2]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf
   Google Scholar
• Giacomini KM, Huang SM, Tweedie DJ, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9:215–236.
   PubMed Web of Science ®Google Scholar