Transporter-mediated Natural Product-Drug Interactions

Abstract

The increasing use of natural products in clinical practice has raised great concerns about the potential natural product-drug interactions (NDIs). Drug transporters mediate the transmembrane passage of a broad range of drugs, and thus are important determinants for drug pharmacokinetics and pharmacodynamics. Generally, transporters can be divided into ATP binding cassette (ABC) family and solute carrier (SLC) family. Numerous natural products have been identified as inhibitors, substrates, inducers, and/or activators of drug transporters. This review article aims to provide a comprehensive summary of the recent progress on the research of NDIs, focusing on the main drug transporters, such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter 1 and 3 (OAT1/OAT3), organic anion-transporting polypeptide 1B1 and 1B3 (OATP1B1/OATP1B3), organic cation transporter 2 (OCT2), multidrug and toxin extrusion protein 1 and 2-K (MATE1/MATE2-K). Additionally, the challenges and strategies of studying NDIs are also discussed.

Key words

natural products - drug transporters - natural product-drug interactions - solute carrier transporter - ATP-binding cassette transporter

Publikationsverlauf

Eingereicht: 23. September 2021

Angenommen nach Revision: 17. März 2022

Accepted Manuscript online:
18. März 2022

Artikel online veröffentlicht:
08. Dezember 2022

• References

• 1 Li J, Long X, Hu J, Bi J, Zhou T, Guo X, Han C, Huang J, Wang T, Xiong N, Lin Z. Multiple pathways for natural product treatment of Parkinsonʼs disease: A mini review. Phytomedicine 2019; 60: 152954
• 2 Mondal S, Bandyopadhyay S, Ghosh MK, Mukhopadhyay S, Roy S, Mandal C. Natural products: promising resources for cancer drug discovery. Anticancer Agents Med Chem 2012; 12: 49-75
• 3 Zha W. Transporter-mediated natural product-drug interactions for the treatment of cardiovascular diseases. J Food Drug Anal 2018; 26: S32-S44
• 4 Jadeja R, Devkar RV, Nammi S. Herbal medicines for the treatment of nonalcoholic steatohepatitis: current scenario and future prospects. Evid Based Complement Alternat Med 2014; 2014: 648308
• 5 Hao S, Zhang C, Song H. Natural products improving hyperuricemia with hepatorenal dual effects. Evid Based Complement Alternat Med 2016; 2016: 7390504
• 6 van Breemen RB, Muchiri RN, Bates TA, Weinstein JB, Leier HC, Farley S, Tafesse FG. Cannabinoids block cellular entry of SARS-CoV-2 and the emerging variants. J Nat Prod 2022; 85: 176-184
• 7 Lahlou M. Screening of natural products for drug discovery. Expert Opin Drug Discov 2007; 2: 697-705
• 8 DeGorter MK, Xia CQ, Yang JJ, Kim RB. Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol 2012; 52: 249-273
• 9 International Transporter Consortium. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L. Membrane transporters in drug development. Nat Rev Drug Discov 2010; 9: 215-236
• 10 Nigam SK. What do drug transporters really do?. Nat Rev Drug Discov 2015; 14: 29-44
• 11 Liang Y, Li S, Chen L. The physiological role of drug transporters. Protein Cell 2015; 6: 334-350
• 12 Schlessinger A, Khuri N, Giacomini KM, Sali A. Molecular modeling and ligand docking for solute carrier (SLC) transporters. Curr Top Med Chem 2013; 13: 843-856
• 13 Strazielle N, Ghersi-Egea JF. Efflux transporters in blood-brain interfaces of the developing brain. Front Neurosci 2015; 9: 21
• 14 Silva R, Vilas-Boas V, Carmo H, Dinis-Oliveira RJ, Carvalho F, de Lourdes Bastos M, Remião F. Modulation of P-glycoprotein efflux pump: Induction and activation as a therapeutic strategy. Pharmacol Ther 2015; 149: 1-123
• 15 Sudsakorn S, Bahadduri P, Fretland J, Lu C. 2020 FDA Drug-drug interaction guidance: A comparison analysis and action plan by pharmaceutical industrial scientists. Curr Drug Metab 2020; 21: 403-426
• 16 Cole S, Kerwash E, Andersson A. A summary of the current drug interaction guidance from the European Medicines Agency and considerations of future updates. Drug Metab Pharmacokinet 2020; 35: 2-11
• 17 Wu X, Ma J, Ye Y, Lin G. Transporter modulation by Chinese herbal medicines and its mediated pharmacokinetic herb-drug interactions. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1026: 236-253
• 18 Tachjian A, Maria V, Jahangir A. Use of herbal products and potential interactions in patients with cardiovascular diseases. J Am Coll Cardiol 2010; 55: 515-525
• 19 McChesney JD. Natural products in drug discovery–organizing for success. P R Health Sci J 2002; 21: 91-95
• 20 Negroni MS, Marengo A, Caruso D, Tayar A, Rubiolo P, Giavarini F, Persampieri S, Sangiovanni E, Davanzo F, Carugo S, Colombo ML, DellʼAgli M. High digoxinemia without major complications. Case Rep Cardiol 2019; 2019: 9707428
• 21 Renslo AR. Antimalarial drug discovery: From quinine to the dream of eradication. ACS Med Chem Lett 2013; 4: 1126-1128
• 22 Oyebanji BO, Saba AB, Oridupa OA. Studies on the anti-inflammatory, analgesic and antipyrexic activities of betulinic acid derived from Tetracera potatoria. Afr J Tradit Complement Altern Med 2014; 11: 30-33
• 23 Flisberg P, Rudin A, Linner R, Lundberg CJF. Pain relief and safety after major surgery. A prospective study of epidural and intravenous analgesia in 2696 patients. Acta Anaesthesiol Scand 2003; 47: 457-465
• 24 Takakura AC, Moreira TS, Laitano SC, De Luca Júnior LA, Menani JV. Central muscarinic receptors signal pilocarpine-induced salivation. J Dent Res 2003; 82: 993-997
• 25 Barbuti AM, Chen ZS. Paclitaxel through the ages of anticancer therapy: Exploring its role in chemoresistance and radiation therapy. Cancers (Basel) 2015; 7: 2360-2371
• 26 Nothias LF, Knight R, Dorrestein PC. Antibiotic discovery is a walk in the park. Proc Natl Acad Sci U S A 2016; 113: 14477-14479
• 27 Altmann KH. Drugs from the oceans: Marine natural products as leads for drug discovery. Chimia (Aarau) 2017; 71: 646-652
• 28 Pope JE, Deer TR. Ziconotide: A clinical update and pharmacologic review. Expert Opin Pharmacother 2013; 14: 957-966
• 29 Alonso-Alvarez S, Pardal E, Sanchez-Nieto D, Navarro M, Caballero MD, Mateos MV. Plitidepsin: Design, development, and potential place in therapy. Drug Des Devel Ther 2017; 11: 253-264
• 30 Sweet DH. Organic anion transporter (Slc22a) family members as mediators of toxicity. Toxicol Appl Pharmacol 2005; 204: 198-215
• 31 Ikarashi R, Shibasaki K, Yamaguchi A. Immunohistochemical studies of organic anion transporters and urate transporter 1 expression in human salivary gland. Acta Odontol Scand 2013; 71: 312-316
• 32 Bush KT, Wu W, Lun C, Nigan SK. The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut-liver-kidney axis. J Biol Chem 2017; 292: 15789-15803
• 33 Burckhardt G. Drug transport by Organic Anion Transporters (OATs). Pharmacol Ther 2012; 136: 106-130
• 34 Lu H, Lu Z, Li X, Li G, Qiao Y, Borris RP, Zhang Y. Interactions of 172 plant extracts with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8): a study on herb-drug interactions. PeerJ 2017; 5: e3333
• 35 Li X, Qiao Y, Wang X, Ma R, Li T, Zhang Y, Borris RP. Dihydrophenanthrenes from Juncus effusus as Inhibitors of OAT1 and OAT3. J Nat Prod 2019; 82: 832-839
• 36 Wang L, Sweet DH. Interaction of natural dietary and herbal anionic compounds and flavonoids with human organic anion transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11). Evid Based Complement Alternat Med 2013; 2013: 612527
• 37 Qiao Y, Liu X, Li X, Wang X, Li C, Khutsishvili M, Alizade V, Atha D, Zhang Y, Borris RP. Biflavonoids from Juniperus oblonga inhibit organic anion transporter 3. Biochem Biophys Res Commun 2019; 509: 931-936
• 38 Li C, Wang X, Bi Y, Yu H, Wei J, Zhang Y, Han L, Zhang Y. Potent inhibitors of organic anion transporters 1 and 3 from natural compounds and their protective effect on aristolochic acid nephropathy. Toxicol Sci 2020; 175: 279-291
• 39 Wang L, Sweet DH. Competitive inhibition of human organic anion transporters 1 (SLC22A6), 3 (SLC22A8) and 4 (SLC22A11) by major components of the medicinal herb Salvia miltiorrhiza (Danshen). Drug Metab Pharmacokinet 2013; 28: 220-228
• 40 Li X, Wang X, Li C, Khutsishvili M, Fayvush G, Atha D, Zhang Y, Borris RP. Unusual flavones from Primula macrocalyx as inhibitors of OAT1 and OAT3 and as antifungal agents against candida rugosa. Sci Rep 2019; 9: 9230
• 41 Wang X, Han L, Li G, Peng W, Gao X, Klaassen CD, Fan G, Zhang Y. From the cover: Identification of natural products as inhibitors of human Organic Anion Transporters (OAT1 and OAT3) and their protective effect on mercury-induced toxicity. Toxicol Sci 2018; 161: 321-334
• 42 Nguyen JT, Tian DD, Tanna RS, Hadi DL, Bansal S, Calamia JC, Arian CM, Shireman LM, Molnár B, Horváth M, Kellogg JJ, Layton ME, White JR, Cech NB, Boyce RD, Unadkat JD, Thummel KE, Paine MF. Assessing transporter-mediated natural product-drug interactions via In vitro-In vivo extrapolation: Clinical evaluation with a probe cocktail. Clin Pharmacol Ther 2021; 109: 1342-1352
• 43 Konig J. Uptake transporters of the human OATP family: molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms. Handb Exp Pharmacol 2011; 201: 1-28
• 44 Lee W, Ha JM, Sugiyama Y. Post-translational regulation of the major drug transporters in the families of organic anion transporters and organic anion-transporting polypeptides. J Biol Chem 2020; 295: 17349-17364
• 45 Oswald S. Organic Anion Transporting Polypeptide (OATP) transporter expression, localization and function in the human intestine. Pharmacol Ther 2019; 195: 39-53
• 46 Clarke JD, Novak P, Lake AD, Hardwick RN, Cherrington NJ. Impaired N-linked glycosylation of uptake and efflux transporters in human non-alcoholic fatty liver disease. Liver Int 2017; 37: 1074-1081
• 47 Brenner S, Klameth L, Riha J, Schölm M, Hamilton G, Bajna E, Ausch C, Reiner A, Jäger W, Thalhammer T, Buxhofer-Ausch V. Specific expression of OATPs in primary small cell lung cancer (SCLC) cells as novel biomarkers for diagnosis and therapy. Cancer Lett 2015; 356: 517-524
• 48 Lee W, Belkhiri A, Lockhart AC, Merchant N, Glaeser H, Harris EI, Washington MK, Brunt EM, Zaika A, Kim RB, El-Rifai W. Overexpression of OATP1B3 confers apoptotic resistance in colon cancer. Cancer Res 2008; 68: 10315-10323
• 49 Hamada A, Sissung T, Price DK, Danesi R, Chau CH, Sharifi N, Venzon D, Maeda K, Nagao K, Sparreboom A, Mitsuya H, Dahut WL, Figg WD. Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer. Clin Cancer Res 2008; 14: 3312-3318
• 50 Muto M, Onogawa T, Suzuki T, Ishida T, Rikiyama T, Katayose Y, Ohuchi N, Sasano H, Abe T, Unno M. Human liver-specific organic anion transporter-2 is a potent prognostic factor for human breast carcinoma. Cancer Sci 2007; 98: 1570-1576
• 51 Montonye ML, Tian DD, Arman T, Lynch KD, Hagenbuch B, Paine MF, Clarke JD. A pharmacokinetic natural product-disease-drug interaction: A double hit of silymarin and nonalcoholic steatohepatitis on hepatic transporters in a rat model. J Pharmacol Exp Ther 2019; 371: 385-393
• 52 Bajraktari-Sylejmani G, Weiss J. Potential risk of food-drug interactions: Citrus polymethoxyflavones and flavanones as inhibitors of the Organic Anion Transporting Polypeptides (OATP) 1B1, 1B3, and 2B1. Eur J Drug Metab Pharmacokinet 2020; 45: 809-815
• 53 Mandery K, Balk B, Bujok K, Schmidt I, Fromm MF, Glaeser H. Inhibition of hepatic uptake transporters by flavonoids. Eur J Pharm Sci 2012; 46: 79-85
• 54 Xiang Y, Liu S, Yang J, Wang Z, Zhang H, Gui C. Investigation of the interactions between flavonoids and human organic anion transporting polypeptide 1B1 using fluorescent substrate and 3D-QSAR analysis. Biochim Biophys Acta Biomembr 2020; 1862: 183210
• 55 Fan L, Zhang W, Guo D, Tan ZR, Xu P, Li Q, Liu YZ, Zhang L, He TY, Hu DL, Wang D, Zhou HH. The effect of herbal medicine baicalin on pharmacokinetics of rosuvastatin, substrate of organic anion-transporting polypeptide 1B1. Clin Pharmacol Ther 2008; 83: 471-476
• 56 Misaka S, Yatabe J, Müller F, Takano K, Kawabe K, Glaeser H, Yatabe MS, Onoue S, Werba JP, Watanabe H, Yamada S, Fromm MF, Kimura J. Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects. Clin Pharmacol Ther 2014; 95: 432-438
• 57 Kim TE, Ha N, Kim Y, Kim H, Lee JW, Jeon JY, Kim MG. Effect of epigallocatechin-3-gallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers. Drug Des Devel Ther 2017; 11: 1409-1416
• 58 Yonezawa A, Inui K. Organic cation transporter OCT/SLC22A and H(+)/organic cation antiporter MATE/SLC47A are key molecules for nephrotoxicity of platinum agents. Biochem Pharmacol 2011; 81: 563-568
• 59 Motohashi H, Inui K. Organic cation transporter OCTs (SLC22) and MATEs (SLC47) in the human kidney. AAPS J 2013; 15: 581-588
• 60 Chen Y, Li C, Yi Y, Du W, Jiang H, Zeng S, Zhou H. Organic cation transporter 1 and 3 contribute to the high accumulation of dehydrocorydaline in the heart. Drug Metab Dispos 2020; 48: 1074-1083
• 61 Lechner C, Ishiguro N, Fukuhara A, Shimizu H, Ohtsu N, Takatani M, Nishiyama K, Washio I, Yamamura N, Kusuhara H. Impact of experimental conditions on the evaluation of interactions between multidrug and toxin extrusion proteins and candidate drugs. Drug Metab Dispos 2016; 44: 1381-1389
• 62 Elsby R, Chidlaw S, Outteridge S, Pickering S, Radcliffe A, Sullivan R, Jones H, Butler P. Mechanistic in vitro studies confirm that inhibition of the renal apical efflux transporter multidrug and toxin extrusion (MATE) 1, and not altered absorption, underlies the increased metformin exposure observed in clinical interactions with cimetidine, trimethoprim or pyrimethamine. Pharmacol Res Perspect 2017; 5: e00357
• 63 Jin S, Lee S, Jeon JH, Kim H, Choi MK, Song IS. Enhanced intestinal permeability and plasma concentration of metformin in rats by the repeated administration of red ginseng extract. Pharmaceutics 2019; 11: 189
• 64 Knop J, Misaka S, Singer K, Hoier E, Müller F, Glaeser H, König J, Fromm MF. Inhibitory effects of green tea and (−)-epigallocatechin gallate on transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-glycoprotein. PLoS One 2015; 10: e0139370
• 65 Wang H, Zhu C, Ying Y, Luo L, Huang D, Luo Z. Metformin and berberine, two versatile drugs in treatment of common metabolic diseases. Oncotarget 2018; 9: 10135-10146
• 66 Shi R, Xu Z, Xu X, Jin J, Zhao Y, Wang T, Li Y, Ma Y. Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. Eur J Pharm Sci 2019; 127: 282-290
• 67 Liang X, Giacomini KM. Transporters involved in metformin pharmacokinetics and treatment response. J Pharm Sci 2017; 106: 2245-2250
• 68 Lin JH, Yamazaki M. Clinical relevance of P-glycoprotein in drug therapy. Drug Metab Rev 2003; 35: 417-454
• 69 Mao Q, Unadkat JD. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport–an update. AAPS J 2015; 17: 65-82
• 70 Rocchi E, Khodjakov A, Volk EL, Yang CH, Litman T, Bates SE, Schneider E. The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane. Biochem Biophys Res Commun 2000; 271: 42-46
• 71 Bruyère A, Declèves X, Bouzom F, Ball K, Marques C, Treton X, Pocard M, Valleur P, Bouhnik Y, Panis Y, Scherrmann JM, Mouly S. Effect of variations in the amounts of P-glycoprotein (ABCB1), BCRP (ABCG2) and CYP3A4 along the human small intestine on PBPK models for predicting intestinal first pass. Mol Pharm 2010; 7: 1596-1607
• 72 Huls M, Brown CD, Windass AS, Sayer R, van den Heuvel JJ, Heemskerk S, Russel FG, Masereeuw R. The breast cancer resistance protein transporter ABCG2 is expressed in the human kidney proximal tubule apical membrane. Kidney Int 2008; 73: 220-225
• 73 Xiong J, Mao DA, Liu LQ. Research progress on the role of ABC transporters in the drug resistance mechanism of intractable epilepsy. Biomed Res Int 2015; 2015: 194541
• 74 Limtrakul P, Khantamat O, Pintha K. Inhibition of P-glycoprotein function and expression by kaempferol and quercetin. J Chemother 2005; 17: 86-95
• 75 Iriti M, Kubina R, Cochis A, Sorrentino R, Varoni EM, Kabała-Dzik A, Azzimonti B, Dziedzic A, Rimondini L, Wojtyczka RD. Rutin, a quercetin glycoside, restores chemosensitivity in human breast cancer cells. Phytother Res 2017; 31: 1529-1538
• 76 Sjostedt N, Holvikari K, Tammela P, Kidron H. Inhibition of breast cancer resistance protein and multidrug resistance associated protein 2 by natural compounds and their derivatives. Mol Pharm 2017; 14: 135-146
• 77 Kusuhara H, Furuie H, Inano A, Sunagawa A, Yamada S, Wu C, Fukizawa S, Morimoto N, Ieiri I, Morishita M, Sumita K, Mayahara H, Fujita T, Maeda K, Sugiyama Y. Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP. Br J Pharmacol 2012; 166: 1793-1803
• 78 Chang YT, Wang CCN, Wang JY, Lee TE, Cheng YY, Morris-Natschke SL, Lee KH, Hung CC. Tenulin and isotenulin inhibit P-glycoprotein function and overcome multidrug resistance in cancer cells. Phytomedicine 2019; 53: 252-262
• 79 Goebel J, Chmielewski J, Hrycyna CA. The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors. Cancer Drug Resist 2021; 4: 784-804
• 80 Podszun MC, Jakobi M, Birringer M, Weiss J, Frank J. The long chain alpha-tocopherol metabolite alpha-13′-COOH and gamma-tocotrienol induce P-glycoprotein expression and activity by activation of the pregnane X receptor in the intestinal cell line LS 180. Mol Nutr Food Res 2017;
• 81 Qosa H, Batarseh YS, Mohyeldin MM, El Sayed KA, Keller JN, Kaddoumi A. Oleocanthal enhances amyloid-beta clearance from the brains of TgSwDI mice and in vitro across a human blood-brain barrier model. ACS Chem Neurosci 2015; 6: 1849-1859
• 82 Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR. Drug interaction between St. Johnʼs wort and cyclosporine. Ann Pharmacother 2000; 34: 1013-1016
• 83 Igel S, Drescher S, Mürdter T, Hofmann U, Heinkele G, Tegude H, Glaeser H, Brenner SS, Somogyi AA, Omari T, Schäfer C, Eichelbaum M, Fromm MF. Increased absorption of digoxin from the human jejunum due to inhibition of intestinal transporter-mediated efflux. Clin Pharmacokinet 2007; 46: 777-785
• 84 Mordel A, Halkin H, Zulty L, Amog S, Ezra D. Quinidine enhances digitalis toxicity at therapeutic serum digoxin levels. Clin Pharmacol Ther 1993; 53: 457-462
• 85 He X, Mo L, Li ZY, Tan ZR, Chen Y, Ouyang DS. Effects of curcumin on the pharmacokinetics of talinolol in human with ABCB1 polymorphism. Xenobiotica 2012; 42: 1248-1254
• 86 Davis MW, Wason S, Digiacinto JL. Colchicine-antimicrobial drug interactions: What pharmacists need to know in treating gout. Consult Pharm 2013; 28: 176-183
• 87 Qiu F, Zeng J, Liu S, He M, Zhu L, Ye Y, Miao P, Shen S, Jiang J. Effects of danshen ethanol extract on the pharmacokinetics of fexofenadine in healthy volunteers. Evid Based Complement Alternat Med 2014; 2014: 473213
• 88 Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 2009; 136: 521-534
• 89 Jin X, Luong TL, Reese N, Gaona H, Collazo-Velez V, Vuong C, Potter B, Sousa JC, Olmeda R, Li Q, Xie L, Zhang J, Zhang P, Reichard G, Melendez V, Marcsisin SR, Pybus BS. Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations. J Pharmacol Toxicol Methods 2014; 70: 188-194
• 90 Elsby R, Surry DD, Smith VN, Gray AJ. Validation and application of Caco-2 assays for the in vitro evaluation of development candidate drugs as substrates or inhibitors of P-glycoprotein to support regulatory submissions. Xenobiotica 2008; 38: 1140-1164
• 91 Maubon N, Le Vee M, Fossati L, Audry M, Le Ferrec E, Bolze S, Fardel O. Analysis of drug transporter expression in human intestinal Caco-2 cells by real-time PCR. Fundam Clin Pharmacol 2007; 21: 659-663
• 92 Ye D, Harder A, Fang Z, Weinheimer M, Laplanche L, Mezler M. Characterization and validation of canine P-glycoprotein-deficient MDCK II cell lines for efflux substrate screening. Pharm Res 2020; 37: 194
• 93 Gartzke D, Fricker G. Establishment of optimized MDCK cell lines for reliable efflux transport studies. J Pharm Sci 2014; 103: 1298-1304
• 94 Kuteykin-Teplyakov K, Luna-Tortos C, Ambroziak K, Loscher W. Differences in the expression of endogenous efflux transporters in MDR1-transfected versus wildtype cell lines affect P-glycoprotein mediated drug transport. Br J Pharmacol 2010; 160: 1453-1463
• 95 Glavinas H, Kis E, Pál A, Kovács R, Jani M, Vági E, Molnár E, Bánsághi S, Kele Z, Janáky T, Báthori G, von Richter O, Koomen GJ, Krajcsi P. ABCG2 (breast cancer resistance protein/mitoxantrone resistance-associated protein) ATPase assay: a useful tool to detect drug-transporter interactions. Drug Metab Dispos 2007; 35: 1533-1542
• 96 Xiao Y, Davidson R, Smith A, Pereira D, Zhao S, Soglia J, Gebhard D, de Morais S, Duignan DB. A 96-well efflux assay to identify ABCG2 substrates using a stably transfected MDCK II cell line. Mol Pharm 2006; 3: 45-54
• 97 Grandvuinet AS, Vestergaard HT, Rapin N, Steffansen B. Intestinal transporters for endogenic and pharmaceutical organic anions: The challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions. J Pharm Pharmacol 2012; 64: 1523-1548
• 98 Bi L, Chen J, Yuan X, Jiang Z, Chen W. Salvianolic acid A positively regulates PTEN protein level and inhibits growth of A549 lung cancer cells. Biomed Rep 2013; 1: 213-217
• 99 Muller J, Lips KS, Metzner L, Neubert RHH, Koepsell H, Brandsch M. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol 2005; 70: 1851-1860
• 100 Hagos Y, Stein D, Ugele B, Burckhardt G, Bahn A. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol 2007; 18: 430-439
• 101 Shen H, Lee FY, Gan J. Ixabepilone, a novel microtubule-targeting agent for breast cancer, is a substrate for P-glycoprotein (P-gp/MDR1/ABCB1) but not breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther 2011; 337: 423-432
• 102 Singh N, Chatterjee M, Sundar S. The overexpression of genes of thiol metabolism contribute to drug resistance in clinical isolates of visceral leishmaniasis (kala azar) in India. Parasit Vectors 2014; 7: 596
• 103 Konig J, Zolk O, Singer K, Hommann C, Fromm MF. Double-transfected MDCK cells expressing human OCT1/MATE1 or OCT2/MATE1: Determinants of uptake and transcellular translocation of organic cations. Br J Pharmacol 2011; 163: 546-555
• 104 Letschert K, Komatsu M, Hummel-Eisenbeiss J, Keppler D. Vectorial transport of the peptide CCK-8 by double-transfected MDCKII cells stably expressing the organic anion transporter OATP1B3 (OATP8) and the export pump ABCC2. J Pharmacol Exp Ther 2005; 313: 549-556
• 105 Haberkorn B, Fromm MF, Konig J. Transport of drugs and endogenous compounds mediated by human OCT1: Studies in single- and double-transfected cell models. Front Pharmacol 2021; 12: 662535
• 106 Hirouchi M, Kusuhara H, Onuki R, Ogilvie BW, Parkinson A, Sugiyama Y. Construction of triple-transfected cells [organic anion-transporting polypeptide (OATP) 1B1/multidrug resistance-associated protein (MRP) 2/MRP3 and OATP1B1/MRP2/MRP4] for analysis of the sinusoidal function of MRP3 and MRP4. Drug Metab Dispos 2009; 37: 2103-2111
• 107 Kopplow K, Letschert K, Konig J, Walter B, Keppler D. Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. Mol Pharmacol 2005; 68: 1031-1038
• 108 Swift B, Pfeifer ND, Brouwer KL. Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity. Drug Metab Rev 2010; 42: 446-471
• 109 Fukuda H, Ohashi R, Tsuda-Tsukimoto M, Tamai I. Effect of plasma protein binding on in vitro-in vivo correlation of biliary excretion of drugs evaluated by sandwich-cultured rat hepatocytes. Drug Metab Dispos 2008; 36: 1275-1282
• 110 Iwasaki S, Hirabayashi H, Amano N. Quantitative prediction of the extent of drug-drug interaction using a physiologically based pharmacokinetic model that includes inhibition of drug metabolism determined in cryopreserved hepatocytes. Xenobiotica 2018; 48: 770-780
• 111 Cerec V, Glaise D, Garnier D, Morosan S, Turlin B, Drenou B, Gripon P, Kremsdorf D, Guguen-Guillouzo C, Corlu A. Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor. Hepatology 2007; 45: 957-967
• 112 Wang D. Current research method in transporter study. Adv Exp Med Biol 2019; 1141: 203-240
• 113 Luo Z, Liu Y, Zhao B, Tang M, Dong H, Zhang L, Lv B, Wei L. Ex vivo and in situ approaches used to study intestinal absorption. J Pharmacol Toxicol Methods 2013; 68: 208-216
• 114 Lau YY, Wu CY, Okochi H, Benet LZ. Ex situ inhibition of hepatic uptake and efflux significantly changes metabolism: Hepatic enzyme-transporter interplay. J Pharmacol Exp Ther 2004; 308: 1040-1045
• 115 Jaiswal S, Sharma A, Shukla M, Vaghasiya K, Rangaraj N, Lal J. Novel pre-clinical methodologies for pharmacokinetic drug-drug interaction studies: Spotlight on “humanized” animal models. Drug Metab Rev 2014; 46: 475-493
• 116 van de Steeg E, van Esch A, Wagenaar E, Kenworthy KE, Schinkel AH. Influence of human OATP1B1, OATP1B3, and OATP1A2 on the pharmacokinetics of methotrexate and paclitaxel in humanized transgenic mice. Clin Cancer Res 2013; 19: 821-832
• 117 Gameiro M, Silva R, Rocha-Pereira C, Carmo H, Carvalho F, Bastos ML, Remião F. Cellular Models and In vitro Assays for the Screening of modulators of P-gp, MRP1 and BCRP. Molecules 2017; 22: 600
• 118 Vilas-Boas V, Silva R, Palmeira A, Sousa E, Ferreira LM, Branco PS, Carvalho F, Bastos Mde L, Remião F. Development of novel rifampicin-derived P-glycoprotein activators/inducers. synthesis, in silico analysis and application in the RBE4 cell model, using paraquat as substrate. PLoS One 2013; 8: e74425
• 119 Silva R, Carmo H, Vilas-Boas V, Barbosa DJ, Palmeira A, Sousa E, Carvalho F, Bastos Mde L, Remião F. Colchicine effect on P-glycoprotein expression and activity: in silico and in vitro studies. Chem Biol Interact 2014; 218: 50-62
• 120 Zhang YK, Zhang XY, Zhang GN, Wang YJ, Xu H, Zhang D, Shukla S, Liu L, Yang DH, Ambudkar SV, Chen ZS. Selective reversal of BCRP-mediated MDR by VEGFR-2 inhibitor ZM323881. Biochem Pharmacol 2017; 132: 29-37
• 121 Zhang X, Shirahatti NV, Mahadevan D, Wright SH. A conserved glutamate residue in transmembrane helix 10 influences substrate specificity of rabbit OCT2 (SLC22A2). J Biol Chem 2005; 280: 34813-34822
• 122 Gupta CL, Akhtar S, Bajpai P. In silico protein modeling: possibilities and limitations. EXCLI J 2014; 13: 513-515
• 123 MacKay K, Kusalik A. Computational methods for predicting 3D genomic organization from high-resolution chromosome conformation capture data. Brief Funct Genomics 2020; 19: 292-308
• 124 Gueniche N, Huguet A, Bruyere A, Habauzit D, Le Hegarat L, Fardel O. Comparative in silico prediction of P-glycoprotein-mediated transport for 2010–2020 US FDA-approved drugs using six Web-tools. Biopharm Drug Dispos 2021; 42: 393-398
• 125 Werba JP, Misaka S, Giroli MG, Shimomura K, Amato M, Simonelli N, Vigo L, Tremoli E. Update of green tea interactions with cardiovascular drugs and putative mechanisms. J Food Drug Anal 2018; 26: S72-S77
• 126 Fardel O, Kolasa E, Le Vee M. Environmental chemicals as substrates, inhibitors or inducers of drug transporters: Implication for toxicokinetics, toxicity and pharmacokinetics. Expert Opin Drug Metab Toxicol 2012; 8: 29-46
• 127 Le Vee M, Bacle A, Bruyere A, Fardel O. Neonicotinoid pesticides poorly interact with human drug transporters. J Biochem Mol Toxicol 2019; 33: e22379
• 128 Chedik L, Bruyere A, Le Vee M, Stieger B, Denizot C, Parmentier Y, Potin S, Fardel O. Inhibition of human drug transporter activities by the pyrethroid pesticides allethrin and tetramethrin. PLoS One 2017; 12: e0169480
• 129 Malati CY, Robertson SM, Hunt JD, Chairez C, Alfaro RM, Kovacs JA, Penzak SR. Influence of Panax ginseng on cytochrome P450 (CYP)3A and P-glycoprotein (P-gp) activity in healthy participants. J Clin Pharmacol 2012; 52: 932-939
• 130 Taskar KS, Pilla Reddy V, Burt H, Posada MM, Varma M, Zheng M, Ullah M, Emami Riedmaier A, Umehara KI, Snoeys J, Nakakariya M, Chu X, Beneton M, Chen Y, Huth F, Narayanan R, Mukherjee D, Dixit V, Sugiyama Y, Neuhoff S. Physiologically-based pharmacokinetic models for evaluating membrane transporter mediated drug-drug interactions: Current capabilities, case studies, future opportunities, and recommendations. Clin Pharmacol Ther 2020; 107: 1082-1115