Advertisement

Relevance of Transporters in Clinical Studies

  • Bruno Hagenbuch
Living reference work entry

Abstract

It has become clear that drug disposition is not just a result of passive diffusion and metabolizing enzymes. Numerous transporters were identified in recent years to be involved in the absorption, distribution, and excretion of essentially all drugs. While transporters of the solute carrier (SLC) family are mainly involved in the uptake of drugs into cells, ATP-binding cassette (ABC) transporters are responsible for their efflux. Among the more than 420 SLC and 47 ABC transporters, only about 25 seem to be important for the disposition of over-the-counter and prescription drugs. Among these the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) have identified seven transporters which need to be tested for investigational drugs and an additional five transporters that are considered to be important. Two of the seven transporters, the multidrug resistance protein 1 (MDR1) and the breast cancer resistance protein (BCRP), are ABC transporters. The other five, the organic cation transporter 2 (OCT2), the organic anion transporter 1 (OAT1) and 3 (OAT3), and the organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3), are SLC transporters. If additional transporters become clinically relevant, they may be added by the regulatory agencies to the list or required transporters.

Notes

Acknowledgments

The author would like to acknowledge the National Institutes of Health grant GM077336.

References and Further Reading

  1. Abdullahi W, Davis TP, Ronaldson PT (2017) Functional expression of P-glycoprotein and organic anion transporting polypeptides at the blood-brain barrier: understanding transport mechanisms for improved CNS drug delivery? AAPS J 19:931–939CrossRefPubMedPubMedCentralGoogle Scholar
  2. Amidon GL, Lennernas H, Shah VP et al (1995) A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12:413–420CrossRefPubMedGoogle Scholar
  3. Bednarczyk D (2010) Fluorescence-based assays for the assessment of drug interaction with the human transporters OATP1B1 and OATP1B3. Anal Biochem 405:50–58CrossRefPubMedPubMedCentralGoogle Scholar
  4. Belzer M, Morales M, Jagadish B et al (2013) Substrate-dependent ligand inhibition of the human organic cation transporter OCT2. J Pharmacol Exp Ther 346:300–310CrossRefPubMedPubMedCentralGoogle Scholar
  5. Brouwer KL, Keppler D, Hoffmaster KA et al (2013) In vitro methods to support transporter evaluation in drug discovery and development. Clin Pharmacol Ther 94:95–112CrossRefPubMedGoogle Scholar
  6. Burckhardt G, Burckhardt BC (2011) In vitro and in vivo evidence of the importance of organic anion transporters (OATs) in drug therapy. Handb Exp Pharmacol 201:29–104CrossRefGoogle Scholar
  7. Chun SE, Thakkar N, Oh Y et al (2017) The N-terminal region of organic anion transporting polypeptide 1B3 (OATP1B3) plays an essential role in regulating its plasma membrane trafficking. Biochem Pharmacol 131:98–105CrossRefPubMedGoogle Scholar
  8. Cleophas MC, Joosten LA, Stamp LK et al (2017) ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches. Pharmgenomics Pers Med 10:129–142PubMedPubMedCentralGoogle Scholar
  9. Droge C, Bonus M, Baumann U et al (2017) Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. J Hepatol 67:1253–1264CrossRefPubMedGoogle Scholar
  10. Drozdzik M, Groer C, Penski J et al (2014) Protein abundance of clinically relevant multidrug transporters along the entire length of the human intestine. Mol Pharm 11:3547–3555CrossRefPubMedGoogle Scholar
  11. Fujita T, Urban TJ, Leabman MK et al (2006) Transport of drugs in the kidney by the human organic cation transporter, OCT2 and its genetic variants. J Pharm Sci 95:25–36CrossRefPubMedGoogle Scholar
  12. Giacomini KM, Huang SM, Tweedie DJ et al (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236CrossRefPubMedGoogle Scholar
  13. Gong IY, Kim RB (2013) Impact of genetic variation in OATP transporters to drug disposition and response. Drug Metab Pharmacokinet 28:4–18CrossRefPubMedGoogle Scholar
  14. Gui C, Obaidat A, Chaguturu R et al (2010) Development of a cell-based high-throughput assay to screen for inhibitors of organic anion transporting polypeptides 1B1 and 1B3. Curr Chem Genomics 4:1–8CrossRefPubMedPubMedCentralGoogle Scholar
  15. Hagenbuch B, Stieger B (2013) The SLCO (former SLC21) superfamily of transporters. Mol Asp Med 34:396–412CrossRefGoogle Scholar
  16. Heredi-Szabo K, Glavinas H, Kis E et al (2009) Multidrug resistance protein 2-mediated estradiol-17beta-D-glucuronide transport potentiation: in vitro-in vivo correlation and species specificity. Drug Metab Dispos 37:794–801CrossRefPubMedGoogle Scholar
  17. Hillgren KM, Keppler D, Zur AA et al (2013) Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther 94:52–63CrossRefPubMedGoogle Scholar
  18. Hira D, Terada T (2018) BCRP/ABCG2 and high-alert medications: biochemical, pharmacokinetic, pharmacogenetic, and clinical implications. Biochem Pharmacol 147:201–210CrossRefPubMedGoogle Scholar
  19. Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152–162CrossRefPubMedGoogle Scholar
  20. Koepsell H (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Asp Med 34:413–435CrossRefGoogle Scholar
  21. Lee CA, O’Connor MA, Ritchie TK et al (2015) Breast cancer resistance protein (ABCG2) in clinical pharmacokinetics and drug interactions: practical recommendations for clinical victim and perpetrator drug-drug interaction study design. Drug Metab Dispos 43:490–509CrossRefPubMedGoogle Scholar
  22. Link E, Parish S, Armitage J et al (2008) SLCO1B1 variants and statin-induced myopathy – a genomewide study. N Engl J Med 359:789–799CrossRefPubMedGoogle Scholar
  23. Liu Y, Zheng X, Yu Q et al (2016) Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin. Sci Transl Med 8:348ra397Google Scholar
  24. Lund M, Petersen TS, Dalhoff KP (2017) Clinical implications of P-glycoprotein modulation in drug-drug interactions. Drugs 77:859–883CrossRefPubMedGoogle Scholar
  25. Morgan RE, Trauner M, van Staden CJ et al (2010) Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci 118:485–500CrossRefPubMedGoogle Scholar
  26. Motohashi H, Inui K (2013) Multidrug and toxin extrusion family SLC47: physiological, pharmacokinetic and toxicokinetic importance of MATE1 and MATE2-K. Mol Asp Med 34:661–668CrossRefGoogle Scholar
  27. Nies AT, Koepsell H, Damme K et al (2011) Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handb Exp Pharmacol 201:105–167CrossRefGoogle Scholar
  28. Patel M, Taskar KS, Zamek-Gliszczynski MJ (2016) Importance of hepatic transporters in clinical disposition of drugs and their metabolites. J Clin Pharmacol 56(Suppl 7):S23–S39CrossRefPubMedGoogle Scholar
  29. Pfeifer ND, Hardwick RN, Brouwer KL (2014) Role of hepatic efflux transporters in regulating systemic and hepatocyte exposure to xenobiotics. Annu Rev Pharmacol Toxicol 54:509–535CrossRefPubMedGoogle Scholar
  30. Roninson IB, Chin JE, Choi KG et al (1986) Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells. Proc Natl Acad Sci U S A 83:4538–4542CrossRefPubMedPubMedCentralGoogle Scholar
  31. Roth M, Obaidat A, Hagenbuch B (2012) OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol 165:1260–1287CrossRefPubMedPubMedCentralGoogle Scholar
  32. Saidijam M, Karimi Dermani F, Sohrabi S et al (2018) Efflux proteins at the blood-brain barrier: review and bioinformatics analysis. Xenobiotica 48:506–532CrossRefPubMedGoogle Scholar
  33. Schinkel AH, Jonker JW (2003) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 55:3–29CrossRefPubMedGoogle Scholar
  34. Schinkel AH, Wagenaar E, Mol CA et al (1996) P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97:2517–2524CrossRefPubMedPubMedCentralGoogle Scholar
  35. Sjostedt N, Holvikari K, Tammela P et al (2017) Inhibition of breast cancer resistance protein and multidrug resistance associated protein 2 by natural compounds and their derivatives. Mol Pharm 14:135–146CrossRefPubMedGoogle Scholar
  36. Staud F, Cerveny L, Ahmadimoghaddam D et al (2013) Multidrug and toxin extrusion proteins (MATE/SLC47); role in pharmacokinetics. Int J Biochem Cell Biol 45:2007–2011CrossRefPubMedGoogle Scholar
  37. Stieger B (2011) The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb Exp Pharmacol 201:205–259CrossRefGoogle Scholar
  38. Stieger B, Hagenbuch B (2016) Recent advances in understanding hepatic drug transport. F1000Res 5:2465CrossRefPubMedPubMedCentralGoogle Scholar
  39. Terada T, Hira D (2015) Intestinal and hepatic drug transporters: pharmacokinetic, pathophysiological, and pharmacogenetic roles. J Gastroenterol 50:508–519CrossRefPubMedGoogle Scholar
  40. Ueda K, Cornwell MM, Gottesman MM et al (1986) The mdr1 gene, responsible for multidrug-resistance, codes for P-glycoprotein. Biochem Biophys Res Commun 141:956–962CrossRefPubMedGoogle Scholar
  41. Urquhart BL, Kim RB (2009) Blood-brain barrier transporters and response to CNS-active drugs. Eur J Clin Pharmacol 65:1063–1070CrossRefPubMedGoogle Scholar
  42. van de Steeg E, Stranecky V, Hartmannova H et al (2012) Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 122:519–528CrossRefPubMedPubMedCentralGoogle Scholar
  43. Wagner DJ, Hu T, Wang J (2016) Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics. Pharmacol Res 111:237–246CrossRefPubMedPubMedCentralGoogle Scholar
  44. Wessler JD, Grip LT, Mendell J et al (2013) The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol 61:2495–2502CrossRefPubMedGoogle Scholar
  45. Wolking S, Schaeffeler E, Lerche H et al (2015) Impact of genetic polymorphisms of ABCB1 (MDR1, P-glycoprotein) on drug disposition and potential clinical implications: update of the literature. Clin Pharmacokinet 54:709–735CrossRefPubMedGoogle Scholar
  46. Yee SW, Nguyen AN, Brown C et al (2013) Reduced renal clearance of cefotaxime in asians with a low-frequency polymorphism of OAT3 (SLC22A8). J Pharm Sci 102:3451–3457CrossRefPubMedPubMedCentralGoogle Scholar
  47. Yin J, Wang J (2016) Renal drug transporters and their significance in drug-drug interactions. Acta Pharm Sin B 6:363–373CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, Toxicology and TherapeuticsThe University of Kansas Medical CenterKansas CityUSA

Personalised recommendations