What do drug transporters really do?

Nature Reviews Drug Discovery

Volumn 14, Issue 1, 2014, Pages 29-44

  Nigam, Sanjay K ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ABC TRANSPORTER; ACICLOVIR; ADEFOVIR; ANTIOXIDANT; BREAST CANCER RESISTANCE PROTEIN; CARRIER PROTEIN; CIMETIDINE; DRUG CARRIER; METFORMIN; METHOTREXATE; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 1; PRAVASTATIN; ROSUVASTATIN; SOLUTE CARRIER TRANSPORTER; UNCLASSIFIED DRUG; URIC ACID; DRUG; ORGANIC ANION TRANSPORTER;

ABC GENE; BINDING AFFINITY; CHRONIC KIDNEY DISEASE; DIABETES MELLITUS; DRUG MECHANISM; DRUG PROTEIN BINDING; GENE CLUSTER; GENE CONSTRUCT; GENE FUNCTION; GENE LOCATION; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC CONSERVATION; GENETIC VARIABILITY; GOUT; HUMAN; HYPERTENSION; KNOCKOUT GENE; LIVER DISEASE; METABOLIC SYNDROME X; METABOLOMICS; MUTATIONAL ANALYSIS; NONHUMAN; PHARMACOGENETICS; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN LOCALIZATION; REVIEW; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; SLC GENE; ANIMAL; DRUG INTERACTION; GENETICS; METABOLISM; PHYSIOLOGY; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; ATP-BINDING CASSETTE TRANSPORTERS; BIOLOGICAL TRANSPORT; DRUG INTERACTIONS; HUMANS; MEMBRANE TRANSPORT PROTEINS; ORGANIC ANION TRANSPORTERS; PHARMACEUTICAL PREPARATIONS;

EID: 84925285641     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4461     Document Type: Review

References (256)

1. You, G. & Morris, M. E. (eds) Drug Transporters: Molecular Characterization and Role in Drug Disposition (John Wiley & Sons, 2014).
2. Giacomini, K. M. et al. International Transporter Consortium commentary on clinically important transporter polymorphisms. Clin. Pharmacol. Ther. 94, 23-26 (2013).
3. Giacomini, K. M. et al. Membrane transporters in drug development. Nature Rev. Drug Discov. 9, 215-236 (2010).
4. Morrissey, K. M. et al. The UCSF-FDA TransPortal: a public drug transporter database. Clin. Pharmacol. Ther. 92, 545-546 (2012).
5. Zamek-Gliszczynski, M. J. et al. ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans. Clin. Pharmacol. Ther. 94, 64-79 (2013).
6. Lee, S. C., Zhang, L. & Huang, S. M. in Drug Transporters: Molecular Characterization and Role in Drug Disposition (eds You, G. & Morris, M. E.) 495 (John Wiley & Sons, 2014).
7. Ahn, S. Y. & Nigam, S. K. Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis. Mol. Pharmacol. 76, 481-490 (2009).
8. DeGorter, M. K., Xia, C. Q., Yang, J. J. & Kim, R. B. Drug transporters in drug efficacy and toxicity. Annu. Rev. Pharmacol. Toxicol. 52, 249-273 (2012).
9. Klaassen, C. D. & Aleksunes, L. M. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol. Rev. 62, 1-96 (2010).
10. Koepsell, H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol. Aspects Med. 34, 413-435 (2013).
11. Emami Riedmaier, A., Nies, A. T., Schaeffeler, E. & Schwab, M. Organic anion transporters and their implications in pharmacotherapy. Pharmacol. Rev. 64, 421-449 (2012).
12. Roth, M., Obaidat, A. & Hagenbuch, B. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br. J. Pharmacol. 165, 1260-1287 (2012).
13. VanWert, A. L., Gionfriddo, M. R. & Sweet, D. H. Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm. Drug Dispos. 31, 1-71 (2010).
14. Wu, W., Dnyanmote, A. V. & Nigam, S. K. Remote communication through solute carriers and ATP binding cassette drug transporter pathways: an update on the remote sensing and signaling hypothesis. Mol. Pharmacol. 79, 795-805 (2011).
15. Gottesman, M. M. & Ambudkar, S. V. Overview: ABC transporters and human disease. J. Bioenerg. Biomembr. 33, 453-458 (2001).
16. Seeger, M. A. & van Veen, H. W. Molecular basis of multidrug transport by ABC transporters. Biochim. Biophys. Acta 1794, 725-737 (2009).
17. Borst, P., de Wolf, C. & van de Wetering, K. Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 453, 661-673 (2007).
18. Aller, S. G. et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323, 1718-1722 (2009).
19. Choudhuri, S. & Klaassen, C. D. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int. J. Toxicol. 25, 231-259 (2006).
20. Miller, D. S. Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol. Sci. 31, 246-254 (2010).
21. Sweeney, D. E. et al. Functional maturation of drug transporters in the developing, neonatal, and postnatal kidney. Mol. Pharmacol. 80, 147-154 (2011).
22. Chen, Q. X., Hu, H. H., Zhou, Q., Yu, A. M. & Zeng, S. An overview of ABC and SLC drug transporter gene regulation. Curr. Drug Metab. 14, 253-264 (2013).
23. de Jonge-Peeters, S. D., Kuipers, F., de Vries, E. G. & Vellenga, E. ABC transporter expression in hematopoietic stem cells and the role in AML drug resistance. Crit. Rev. Oncol. Hematol. 62, 214-226 (2007).
24. Burckhardt, G. & Burckhardt, B. C. in Drug Transporters (eds Fromm, M. F. & Kim, R. B.) 29-104 (Springer, 2011).
25. Choi, Y. H. & Yu, A. M. ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development. Curr. Pharm. Des. 20, 793-807 (2013).
26. Hagenbuch, B. & Stieger, B. The SLCO (former SLC21) superfamily of transporters. Mol. Aspects Med. 34, 396-412 (2013).
27. Morrissey, K. M., Stocker, S. L., Wittwer, M. B., Xu, L. & Giacomini, K. M. Renal transporters in drug development. Annu. Rev. Pharmacol. Toxicol. 53, 503-529 (2013).
28. Ahn, S. Y. & Bhatnagar, V. Update on the molecular physiology of organic anion transporters. Curr. Opin. Nephrol. Hypertens. 17, 499-505 (2008).
29. Nigam, S. K. & Bhatnagar, V. How much do we know about drug handling by SLC and ABC drug transporters in children? Clin. Pharmacol. Ther. 94, 27-29 (2013).
30. Lopez-Lopez, E. et al. Polymorphisms in the methotrexate transport pathway: a new tool for MTX plasma level prediction in pediatric acute lymphoblastic leukemia. Pharmacogenet. Genom. 23, 53-61 (2013).
31. Maeda, A. et al. Drug interaction between celecoxib and methotrexate in organic anion transporter 3-transfected renal cells and in rats in vivo. Eur. J. Pharmacol. 640, 168-171 (2010).
32. VanWert, A. L. & Sweet, D. H. Impaired clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender specific impact of reduced folates. Pharm. Res. 25, 453-462 (2008).
33. Vlaming, M. L. et al. Abcc2 (Mrp2), Abcc3 (Mrp3), and Abcg2 (Bcrp1) are the main determinants for rapid elimination of methotrexate and its toxic metabolite 7-hydroxymethotrexate in vivo. Mol. Cancer Ther. 8, 3350-3359 (2009).
34. Kaler, G. et al. Structural variation governs substrate specificity for organic anion transporter (OAT) homologs. Potential remote sensing by OAT family members. J. Biol. Chem. 282, 23841-23853 (2007).
35. Nagle, M. A. et al. Analysis of three-dimensional systems for developing and mature kidneys clarifies the role of OAT1 and OAT3 in antiviral handling. J. Biol. Chem. 286, 243-251 (2011).
36. Vlaming, M. L. et al. Functionally overlapping roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate in vivo. Clin. Cancer Res. 15, 3084-3093 (2009).
37. Vlaming, M. L. et al. Bcrp1;Mdr1a/b;Mrp2 combination knockout mice: altered disposition of the dietary carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine) and its genotoxic metabolites. Mol. Pharmacol. 85, 520-530 (2014).
38. Eraly, S. A. et al. Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J. Biol. Chem. 281, 5072-5083 (2006).
39. Han, Y. F. et al. Association of intergenic polymorphism of organic anion transporter 1 and 3 genes with hypertension and blood pressure response to hydrochlorothiazide. Am. J. Hypertens. 24, 340-346 (2011).
40. Vallon, V. et al. Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am. J. Physiol. Renal Physiol. 294, F867-F873 (2008).
41. Chen, Y. et al. Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenet. Genom. 19, 497-504 (2009).
42. Christensen, M. M. et al. A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin. Pharmacogenet. Genom. 23, 526-534 (2013).
43. Stocker, S. L. et al. The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin. Pharmacol. Ther. 93, 186-194 (2013).
44. Lopez-Nieto, C. E., You, G., Barros, E. J. G., Beier, D. R. & Nigam, S. K. Molecular cloning and characterization of a novel transporter protein with very high expression in the kidney (abstract) J. Am. Soc. Nephrol. 7, 1301 (1996).
45. Lopez-Nieto, C. E. et al. Mus musculus kidney-specific transport protein mRNA (complete cds), accession number U52842.1. NCBI GenBank [online], http://www.ncbi.nlm.nih.gov/gene/?term=U52842.1 (1996).
46. Lopez-Nieto, C. E. et al. Molecular cloning and characterization of NKT, a gene product related to the organic cation transporter family that is almost exclusively expressed in the kidney. J. Biol. Chem. 272, 6471-6478 (1997).
47. Smith, H. W., Finkelstein, N., Aliminosa, L., Crawford, B. & Graber, M. The renal clearances of substituted hippuric acid derivatives and other aromatic acids in dog and man. J. Clin. Invest. 24, 388-404 (1945).
48. Burnell, J. M. & Kirby, W. M. Effectiveness of a new compound, benemid, in elevating serum penicillin concentrations. J. Clin. Invest. 30, 697-700 (1951).
49. Pritchard, J. B. Luminal and peritubular steps in renal transport of p-aminohippurate. Biochim. Biophys. Acta 906, 295-308 (1987).
50. Nigam, S. K. et al. The organic anion transporter (OAT) family: A systems biology perspective. Physiol. Rev. (in the press).
51. Ahn, S. Y., Eraly, S. A., Tsigelny, I. & Nigam, S. K. Interaction of organic cations with organic anion transporters. J. Biol. Chem. 284, 31422-31430 (2009).
52. Truong, D. M., Kaler, G., Khandelwal, A., Swaan, P. W. & Nigam, S. K. Multi-level analysis of organic anion transporters 1, 3, and 6 reveals major differences in structural determinants of antiviral discrimination. J. Biol. Chem. 283, 8654-8663 (2008).
53. Windass, A. S., Lowes, S., Wang, Y. & Brown, C. D. The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. J. Pharmacol. Exp. Ther. 322, 1221-1227 (2007).
54. Bahn, A. et al. Murine renal organic anion transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites. Am. J. Physiol. Cell Physiol. 289, C1075-1084 (2005).
55. Khamdang, S. et al. Interactions of human-and rat-organic anion transporters with pravastatin and cimetidine. J. Pharmacol. Sci. 94, 197-202 (2004).
56. Pavlova, A. et al. Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct. Am. J. Physiol. Renal Physiol. 278, F635-643 (2000).
57. Zalups, R. K. & Ahmad, S. Handling of cysteine S-conjugates of methylmercury in MDCK cells expressing human OAT1. Kidney Int. 68, 1684-1699 (2005).
58. Wong, C. C., Botting, N. P., Orfila, C., Al-Maharik, N. & Williamson, G. Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6). Biochem. Pharmacol. 81, 942-949 (2011).
59. Rizwan, A. N. & Burckhardt, G. Organic anion transporters of the SLC22 family: biopharmaceutical, physiological, and pathological roles. Pharm. Res. 24, 450-470 (2007).
60. Mizuno, N. et al. Human organic anion transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) transport edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and its sulfate conjugate. Drug Metab. Dispos. 35, 1429-1434 (2007).
61. Wikoff, W. R., Nagle, M. A., Kouznetsova, V. L., Tsigelny, I. F. & Nigam, S. K. Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1). J. Proteome Res. 10, 2842-2851 (2011).
62. Nagle, M. A., Wu, W., Eraly, S. A. & Nigam, S. K. Organic anion transport pathways in antiviral handling in choroid plexus in Oat1 (Slc22a6) and Oat3 (Slc22a8) deficient tissue. Neurosci. Lett. 534, 133-138 (2013).
63. Torres, A. M., Dnyanmote, A. V., Bush, K. T., Wu, W. & Nigam, S. K. Deletion of multispecific organic anion transporter Oat1/Slc22a6 protects against mercury-induced kidney injury. J. Biol. Chem. 286, 26391-26395 (2011).
64. Engstrom, K. et al. Polymorphisms in genes encoding potential mercury transporters and urine mercury concentrations in populations exposed to mercury vapor from gold mining. Environ. Health Perspect. 121, 85-91 (2013).
65. Weaver, Y. M., Ehresman, D. J., Butenhoff, J. L & Hagenbuch, B. Roles of rat renal organic anion transporters in transporting perfluorinated carboxylates with different chain lengths. Toxicol. Sci. 113, 305-314 (2010).
66. Brady, K. P. et al. A novel putative transporter maps to the osteosclerosis (oc) mutation and is not expressed in the oc mutant mouse. Genomics 56, 254-261 (1999).
67. Bakhiya, N. et al. Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy. Toxicology 264, 74-79 (2009).
68. Vallon, V. et al. Organic anion transporter 3 contributes to the regulation of blood pressure. J. Am. Soc. Nephrol. 19, 1732-1740 (2008).
69. Vallon, V. et al. A role for the organic anion transporter OAT3 in renal creatinine secretion in mice. Am. J. Physiol. Renal Physiol. 302, F1293-F1299 (2012).
70. Ciarimboli, G. et al. Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. Clin. Cancer Res. 18, 1101-1108 (2012).
71. Eisner, C. et al. Major contribution of tubular secretion to creatinine clearance in mice. Kidney Int. 77, 519-526 (2010).
72. Lepist, E. I. et al. Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat. Kidney Int. 86, 350-357 (2014).
73. Sveinbjornsson, G. et al. Rare mutations associating with serum creatinine and chronic kidney disease. Hum. Mol. Genet. http://dx.doi.org/10.1093/hmg/ddu399 (2014).
74. Cimoch, P. J. et al. Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects. J. Acquir. Immune Def. Syndr. Hum. Retrovirol. 17, 227-234 (1998).
75. Eraly, S. A., Blantz, R. C, Bhatnagar, V & Nigam, S. K. Novel aspects of renal organic anion transporters. Curr. Opin. Nephrol. Hypertens. 12, 551-558 (2003).
76. Maeda, A. et al. Evaluation of the interaction between nonsteroidal anti-inflammatory drugs and methotrexate using human organic anion transporter 3-transfected cells. Eur. J. Pharmacol. 596, 166-172 (2008).
77. Takeda, M. et al. Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J. Pharmacol. Exp. Ther. 302, 666-671 (2002).
78. Yee, S. W. et al. Reduced renal clearance of cefotaxime in Asians with a low-frequency polymorphism of OAT3 (SLC22A8). J. Pharm. Sci. 102, 3451-3457 (2013).
79. Niemi, M., Pasanen, M. K. & Neuvonen, P. J. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol. Rev. 63, 157-181 (2011).
80. Carr, D. F. et al. SLCO1B1 genetic variant associated with statin-induced myopathy: a proof of concept study using the clinical practice research datalink (CPRD). Clin. Pharmacol. Ther. 94, 695-701 (2013).
81. Link, E. et al. SLCO1B1 variants and statin-induced myopathy-a genomewide study. N. Engl. J. Med. 359, 789-799 (2008).
82. Voora, D. et al. The SLCO1B1∗5 genetic variant is associated with statin-induced side effects. J. Am. Coll. Cardiol. 54, 1609-1616 (2009).
83. Huang, M. J. et al. Risk factors for severe hyperbilirubinemia in neonates. Pediatr. Res. 56, 682-689 (2004).
84. Zhang, W. et al. OATP1B1 polymorphism is a major determinant of serum bilirubin level but not associated with rifampicin-mediated bilirubin elevation. Clin. Exp. Pharmacol. Physiol. 34, 1240-1244 (2007).
85. Choi, J. H. et al. A common 5?-UTR variant in MATE2-K is associated with poor response to metformin. Clin. Pharmacol. Ther. 90, 674-684 (2011).
86. Lepper, E. R. et al. Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2. Pharmacogenomics 6, 115-138 (2005).
87. Noguchi, K., Katayama, K., Mitsuhashi, J. & Sugimoto, Y. Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy. Adv. Drug Deliv. Rev. 61, 26-33 (2009).
88. Bosch, T. M., Meijerman, I., Beijnen, J. H. & Schellens, J. H. Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer. Clin. Pharmacokinet. 45, 253-285 (2006).
89. Campa, D. et al. A comprehensive study of polymorphisms in ABCB1, ABCC2 and ABCG2 and lung cancer chemotherapy response and prognosis. Int. J. Cancer 131, 2920-2928 (2012).
90. Kivisto, K. T. & Niemi, M. Influence of drug transporter polymorphisms on pravastatin pharmacokinetics in humans. Pharm. Res. 24, 239-247 (2007).
91. Eraly, S. A. et al. Multiple organic anion transporters contribute to net renal excretion of uric acid. Physiol. Genom. 33, 180-192 (2008).
92. Xu, G. et al. Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)]. Kidney Int. 68, 1491-1499 (2005).
93. Bhatnagar, V. et al. Analyses of 5' regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3). J. Hum. Genet. 51, 575-580 (2006).
94. Kikuchi, R. et al. Regulation of the expression of human organic anion transporter 3 by hepatocyte nuclear factor 1alpha/beta and DNA methylation. Mol. Pharmacol. 70, 887-896 (2006).
95. Martovetsky, G., Tee, J. B. & Nigam, S. K. Hepatocyte nuclear factors 4a and 1a (Hnf4a and Hnf1a) regulate kidney developmental expression of drug-metabolizing enzymes and drug transporters. Mol. Pharmacol. 84, 808-823 (2013).
96. Saito, H. Pathophysiological regulation of renal SLC22A organic ion transporters in acute kidney injury: pharmacological and toxicological implications. Pharmacol. Ther. 125, 79-91 (2010).
97. Schlessinger, A., Yee, S. W., Sali, A. & Giacomini, K. M. SLC classification: an update. Clin. Pharmacol. Ther. 94, 19-23 (2013).
98. Kaler, G. et al. Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions. Biochem. Biophys. Res. Commun. 351, 872-876 (2006).
99. Monte, J. C., Nagle, M. A., Eraly, S. A. & Nigam, S. K. Identification of a novel murine organic anion transporter family member, OAT6, expressed in olfactory mucosa. Biochem. Biophys. Res. Commun. 323, 429-436 (2004).
100. Schnabolk, G. W., Youngblood, G. L. & Sweet, D. H. Transport of estrone sulfate by the novel organic anion transporter Oat6 (Slc22a20). Am. J. Physiol. Renal Physiol. 291, F314-F321 (2006).
101. Enomoto, A. et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 417, 447-452 (2002).
102. Shiraya, K. et al. A novel transporter of SLC22 family specifically transports prostaglandins and co-localizes with 15-hydroxyprostaglandin dehydrogenase in renal proximal tubules. J. Biol. Chem. 285, 22141-22151 (2010).
103. Cha, S. H. et al. Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J. Biol. Chem. 275, 4507-4512 (2000).
104. Nishimura, M. & Naito, S. Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab. Pharmacokinet. 20, 452-477 (2005).
105. Cropp, C. D. et al. Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP. Mol. Pharmacol. 73, 1151-1158 (2008).
106. Kimura, H. et al. Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J. Pharmacol. Exp. Ther. 301, 293-298 (2002).
107. Kobayashi, Y. et al. Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). J. Pharm. Pharmacol. 57, 573-578 (2005).
108. Kobayashi, Y. et al. Renal transport of organic compounds mediated by mouse organic anion transporter 3 (mOat3): further substrate specificity of mOat3. Drug Metab. Dispos. 32, 479-483 (2004).
109. Jonker, J. W., Wagenaar, E., Van Eijl, S. & Schinkel, A. H. Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol. Cell. Biol. 23, 7902-7908 (2003).
110. Farthing, C. A. & Sweet, D. H. Expression and function of organic cation and anion transporters (SLC22 family) in the CNS. Curr. Pharm. Des. 20, 1472-1486 (2014).
111. Massmann, V. et al. The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3. Pflugers Arch. 466, 517-527 (2014).
112. Gilchrist, S. E. & Alcorn, J. Lactation stage-dependent expression of transporters in rat whole mammary gland and primary mammary epithelial organoids. Fundam. Clin. Pharmacol. 24, 205-214 (2010).
113. Lamhonwah, A. M. et al. Upregulation of mammary gland OCTNs maintains carnitine homeostasis in suckling infants. Biochem. Biophys. Res. Commun. 404, 1010-1015 (2011).
114. Crill, C. M. & Helms, R. A. The use of carnitine in pediatric nutrition. Nutr. Clin. Pract. 22, 204-213 (2007).
115. -/-) mice. Mol. Genet. Metab. 92, 315-324 (2007).
116. Alcorn, J., Lu, X., Moscow, J. A. & McNamara, P. J. Transporter gene expression in lactating and nonlactating human mammary epithelial cells using real-time reverse transcription-polymerase chain reaction. J. Pharmacol. Exp. Ther. 303, 487-496 (2002).
117. Riordan, J. R. & Ling, V. Purification of P-glycoprotein from plasma membrane vesicles of Chinese hamster ovary cell mutants with reduced colchicine permeability. J. Biol. Chem. 254, 12701-12705 (1979).
118. Li, Y. & Paxton, J. W. The effects of flavonoids on the ABC transporters: consequences for the pharmacokinetics of substrate drugs. Expert Opin. Drug Metab. Toxicol. 9, 267-285 (2013).
119. Gottesman, M. M. & Ling, V. The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett. 580, 998-1009 (2006).
120. He, S. M., Li, R., Kanwar, J. R. & Zhou, S. F. Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1). Curr. Med. Chem. 18, 439-481 (2011).
121. Poguntke, M., Hazai, E., Fromm, M. F. & Zolk, O. Drug transport by breast cancer resistance protein. Expert Opin. Drug Metab. Toxicol. 6, 1363-1384 (2010).
122. Hu, S. et al. Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin. Cancer Res. 15, 6062-6069 (2009).
123. Ose, A. et al. Limited brain distribution of [3R, 4R, 5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxyl ate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab. Dispos. 37, 315-321 (2009).
124. Chu, X. Y. et al. Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2). J. Pharmacol. Exp. Ther. 317, 579-589 (2006).
125. Lagas, J. S. et al. P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 determine the pharmacokinetics of etoposide. Clin. Cancer Res. 16, 130-140 (2010).
126. Zelcer, N. et al. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc. Natl Acad. Sci. USA 102, 7274-7279 (2005).
127. Lagas, J. S., Vlaming, M. L. & Schinkel, A. H. Pharmacokinetic assessment of multiple ATP-binding cassette transporters: the power of combination knockout mice. Mol. Interv. 9, 136-145 (2009).
128. Kruh, G. D., Belinsky, M. G., Gallo, J. M. & Lee, K. Physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 as determined from recent studies on gene-disrupted mice. Cancer Metastasis Rev. 26, 5-14 (2007).
129. Keppler, D. Multidrug resistance proteins (MRPs, ABCCs): importance for pathophysiology and drug therapy. Handb. Exp. Pharmacol. 201, 299-323 (2011).
130. Tang, S. C., Hendrikx, J. J., Beijnen, J. H. & Schinkel, A. H. Genetically modified mouse models for oral drug absorption and disposition. Curr. Opin. Pharmacol. 13, 853-858 (2013).
131. Mori, K. et al. Kidney-specific expression of a novel mouse organic cation transporter-like protein. FEBS Lett. 417, 371-374 (1997).
132. Kolz, M. et al. Meta-analysis of 28, 141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet. 5, e1000504 (2009).
133. Mount, D. B. The kidney in hyperuricemia and gout. Curr. Opin. Nephrol. Hypertens. 22, 216-223 (2013).
134. Tin, A. et al. Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. Hum. Mol. Genet. 20, 4056-4068 (2011).
135. Vazquez-Mellado, J. et al. Molecular analysis of the SLC22A12 (URAT1) gene in patients with primary gout. Rheumatology 46, 215-219 (2007).
136. Sautin, Y. Y. & Johnson, R. J. Uric acid: the oxidant-antioxidant paradox. Nucleos. Nucleot. Nucl. 27, 608-619 (2008).
137. Mazzali, M. et al. Uric acid and hypertension: cause or effect? Curr. Rheumatol Rep. 12, 108-117 (2010).
138. 2) into milk. Mol. Cell. Biol. 27, 1247-1253 (2007).
139. Ichida, K. et al. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nature Commun. 3, 764 (2012).
140. Hosomi, A., Nakanishi, T., Fujita, T. & Tamai, I. Extra-renal elimination of uric acid via intestinal efflux transporter BCRP/ABCG2. PLoS ONE 7, e30456 (2012).
141. Matsuo, H. et al. Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population. Sci. Transl. Med. 1, 5ra11 (2009).
142. Sakurai, H. Urate transporters in the genomic era. Curr. Opin. Nephrol. Hypertens. 22, 545-550 (2013).
143. Woodward, O. M. et al. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc. Natl Acad. Sci. USA 106, 10338-10342 (2009).
144. Yano, H., Tamura, Y., Kobayashi, K., Tanemoto, M. & Uchida, S. Uric acid transporter ABCG2 is increased in the intestine of the 5/6 nephrectomy rat model of chronic kidney disease. Clin. Exp. Nephrol. 18, 50-55 (2014).
145. Dehghan, A. et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 372, 1953-1961 (2008).
146. Nezu, J. et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nature Genet. 21, 91-94 (1999).
147. Tang, N. L. et al. Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency. Hum. Mol. Genet. 8, 655-660 (1999).
148. Tamai, I. Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Biopharm. Drug Dispos. 34, 29-44 (2013).
149. Tokuhiro, S. et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nature Genet. 35, 341-348 (2003).
150. Peltekova, V. D. et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nature Genet. 36, 471-475 (2004).
151. Waller, S. et al. Evidence for association of OCTN genes and IBD5 with ulcerative colitis. Gut 55, 809-814 (2006).
152. Aouida, M., Poulin, R. & Ramotar, D. The human carnitine transporter SLC22A16 mediates high affinity uptake of the anticancer polyamine analogue bleomycin-A5. J. Biol. Chem. 285, 6275-6284 (2010).
153. Eraly, S. A. & Nigam, S. K. Novel human cDNAs homologous to Drosophila Orct and mammalian carnitine transporters. Biochem. Biophys. Res. Commun. 297, 1159-1166 (2002).
154. Toh, S. et al. Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome. Am. J. Hum. Genet. 64, 739-746 (1999).
155. Schuetz, J. D., Swaan, P. W. & Tweedie, D. J. The role of transporters in toxicity and disease. Drug Metab. Dispos. 42, 541-545 (2014).
156. Keebaugh, A. C. & Thomas, J. W. The evolutionary fate of the genes encoding the purine catabolic enzymes in hominoids, birds, and reptiles. Mol. Biol. Evol. 27, 1359-1369 (2010).
157. Jonker, J. W. et al. Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol. Cell. Biol. 21, 5471-5477 (2001).
158. Sweet, D. H. et al. Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J. Biol. Chem. 277, 26934-26943 (2002).
159. Wu, W. et al. Multispecific drug transporter slc22a8 (oat3) regulates multiple metabolic and signaling pathways. Drug Metab. Dispos. 41, 1825-1834 (2013).
160. Kouznetsova, V. L., Tsigelny, I. F., Nagle, M. A. & Nigam, S. K. Elucidation of common pharmacophores from analysis of targeted metabolites transported by the multispecific drug transporter-Organic anion transporter1 (Oat1). Bioorg. Med. Chem. 19, 3320-3340 (2011).
161. Wright, S. H. & Dantzler, W. H. Molecular and cellular physiology of renal organic cation and anion transport. Physiol. Rev. 84, 987-1049 (2004).
162. Gong, L. et al. Characterization of organic anion-transporting polypeptide (Oatp) 1a1 and 1a4 null mice reveals altered transport function and urinary metabolomic profiles. Toxicol. Sci. 122, 587-597 (2011).
163. Toyohara, T. et al. SLCO4C1 transporter eliminates uremic toxins and attenuates hypertension and renal inflammation. J. Am. Soc. Nephrol. 20, 2546-2555 (2009).
164. van de Steeg, E. et al. Organic anion transporting polypeptide 1a/1b-knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs. J. Clin. Invest. 120, 2942-2952 (2010).
165. Iusuf, D., van de Steeg, E. & Schinkel, A. H. Functions of OATP1A and 1B transporters in vivo: insights from mouse models. Trends Pharmacol. Sci. 33, 100-108 (2012).
166. Hagenbuch, B. Cellular entry of thyroid hormones by organic anion transporting polypeptides. Best Pract. Res. Clin. Endocrinol. Metab. 21, 209-221 (2007).
167. Mayerl, S., Visser, T. J., Darras, V. M., Horn, S. & Heuer, H. Impact of Oatp1c1 deficiency on thyroid hormone metabolism and action in the mouse brain. Endocrinology 153, 1528-1537 (2012).
168. van de Wetering, K., Feddema, W., Helms, J. B., Brouwers, J. F. & Borst, P. Targeted metabolomics identifies glucuronides of dietary phytoestrogens as a major closs of Mrp3 substrates in vivo. Gastroenterology 137, 1725-1735 (2009).
169. Tiwari, A. K., Zhang, R. & Gallo, J. M. Overlapping functions of ABC transporters in topotecan disposition as determined in gene knockout mouse models. Mol. Cancer Ther. 12, 1343-1355 (2013).
170. Jonker, J. W. et al. The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nature Med. 11, 127-129 (2005).
171. Merino, G. et al. Breast cancer resistance protein (BCRP/ABCG2) transports fluoroquinolone antibiotics and affects their oral availability, pharmacokinetics, and milk secretion. Drug Metab. Dispos. 34, 690-695 (2006).
172. Wang, L., Leggas, M., Goswami, M., Empey, P. E. & McNamara, P. J. N-(4-[2-(1, 2, 3, 4-tetrahydro-6, 7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9, 10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) as a chemical ATP-binding cassette transporter family G member 2 (Abcg2) knockout model to study nitrofurantoin transfer into milk. Drug Metab. Dispos. 36, 2591-2596 (2008).
173. Lagas, J. S. et al. P-glycoprotein, multidrug-resistance associated protein 2, Cyp3a, and carboxylesterase affect the oral availability and metabolism of vinorelbine. Mol. Pharmacol. 82, 636-644 (2012).
174. Szallasi, Z., Stelling, J. & Periwal, V. (eds) System Modeling in Cell Biology: From Concepts to Nuts and Bolts (The MIT Press, 2006).
175. Duarte, N. C. et al. Global reconstruction of the human metabolic network based on genomic and bibliomic data. Proc. Natl Acad. Sci. USA 104, 1777-1782 (2007).
176. Thiele, I. et al. A community-driven global reconstruction of human metabolism. Nature Biotech. 31, 419-425 (2013).
177. Ahn, S. Y. et al. Linkage of organic anion transporter-1 to metabolic pathways through integrated 'omics'-driven network and functional analysis. J. Biol. Chem. 286, 31522-31531 (2011).
178. Weiss, J. & Haefeli, W. E. Impact of ATP-binding cassette transporters on human immunodeficiency virus therapy. Int. Rev. Cell. Mol. Biol. 280, 219-279 (2010).
179. Minuesa, G. et al. Drug uptake transporters in antiretroviral therapy. Pharmacol. Ther. 132, 268-279 (2011).
180. Nix, L. M. & Tien, P. C. Metabolic syndrome, diabetes, and cardiovascular risk in HIV. Curr. HIV/AIDS Rep. 11, 271-278 (2014).
181. Buscemi, S. et al. Impact of chronic diuretic treatment on glucose homeostasis. Diabetol Metab. Syndr. 5, 80 (2013).
182. Toyohara, T. et al. Metabolomic profiling of uremic solutes in CKD patients. Hypertens. Res. 33, 944-952 (2010).
183. Jourde-Chiche, N. et al. Protein-bound toxins-update 2009. Semin. Dial. 22, 334-339 (2009).
184. Vanholder, R., Van Laecke, S. & Glorieux, G. What is new in uremic toxicity? Pediatr. Nephrol. 23, 1211-1221 (2008).
185. Banoglu, E. & King, R. S. Sulfation of indoxyl by human and rat aryl (phenol) sulfotransferases to form indoxyl sulfate. Eur. J. Drug Metab. Pharmacokinet. 27, 135-140 (2002).
186. Vecsei, L., Szalardy, L., Fulop, F. & Toldi, J. Kynurenines in the CNS: recent advances and new questions. Nature Rev. Drug Discov. 12, 64-82 (2013).
187. Wang, J. et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J. Biol. Chem. 281, 22021-22028 (2006).
188. Meyer, T. W. & Hostetter, T. H. Uremic solutes from colon microbes. Kidney Int. 81, 949-954 (2012).
189. Geisler, M. & Murphy, A. S. The ABC of auxin transport: the role of p-glycoproteins in plant development. FEBS Lett. 580, 1094-1102 (2006).
190. Zazimalova, E., Murphy, A. S., Yang, H., Hoyerova, K. & Hosek, P. Auxin transporters-why so many? Cold Spring Harb. Perspect. Biol. 2, a001552 (2010).
191. Sparks, E., Wachsman, G. & Benfey, P. N. Spatiotemporal signalling in plant development. Nature Rev. Genet. 14, 631-644 (2013).
192. Duranton, F. et al. Normal and pathologic concentrations of uremic toxins. J. Am. Soc. Nephrol. 23, 1258-1270 (2012).
193. Sharma, K. et al. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J. Am. Soc. Nephrol. 24, 1901-1912 (2013).
194. Beyoglu, D. & Idle, J. R. The metabolomic window into hepatobiliary disease. J. Hepatol. 59, 842-858 (2013).
195. Prentice, K. J. et al. The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction. Cell. Metab. 19, 653-666 (2014).
196. Alebouyeh, M. et al. Expression of human organic anion transporters in the choroid plexus and their interactions with neurotransmitter metabolites. J. Pharmacol. Sci. 93, 430-436 (2003).
197. Redzic, Z. Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 8, 3 (2011).
198. Brandoni, A., Hazelhoff, M. H., Bulacio, R. P. & Torres, A. M. Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis. World J. Gastroenterol. 18, 6387-6397 (2012).
199. Hosseini, E., Grootaert, C., Verstraete, W. & Van de Wiele, T. Propionate as a health-promoting microbial metabolite in the human gut. Nutr. Rev. 69, 245-258 (2011).
200. Hanafy, S., El-Kadi, A. O. & Jamali, F. Effect of inflammation on molecular targets and drug transporters. J. Pharm. Pharm. Sci. 15, 361-375 (2012).
201. Ikemura, K., Nakagawa, E., Kurata, T., Iwamoto, T. & Okuda, M. Altered pharmacokinetics of cimetidine caused by down-regulation of renal rat organic cation transporter 2 (rOCT2) after liver ischemia-reperfusion injury. Drug Metab. Pharmacokinet. 28, 504-509 (2013).
202. Lu, H. & Klaassen, C. Gender differences in mRNA expression of ATP-binding cassette efflux and bile acid transporters in kidney, liver, and intestine of 5/6 nephrectomized rats. Drug Metab. Dispos. 36, 16-23 (2008).
203. Naud, J., Nolin, T. D., Leblond, F. A. & Pichette, V. Current understanding of drug disposition in kidney disease. J. Clin. Pharmacol. 52, 10S-22S (2012).
204. Chahine, S., Seabrooke, S. & O'Donnell, M. J. Effects of genetic knock-down of organic anion transporter genes on secretion of fluorescent organic ions by Malpighian tubules of Drosophila melanogaster. Arch. Insect Biochem. Physiol. 81, 228-240 (2012).
205. Korolnek, T., Zhang, J., Beardsley, S., Scheffer, G. L. & Hamza, I. Control of metazoan heme homeostasis by a conserved multidrug resistance protein. Cell. Metab. 19, 1008-1019 (2014).
206. Shipp, L. E. & Hamdoun, A. ATP-binding cassette (ABC) transporter expression and localization in sea urchin development. Dev. Dyn. 241, 1111-1124 (2012).
207. Hook, J. B. & Hewitt, W. R. Development of mechanisms for drug excretion. Am. J. Med. 62, 497-506 (1977).
208. Zhou, F., Hong, M. & You, G. Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells. Am. J. Physiol. Endocrinol. Metab. 293, E57-E61 (2007).
209. Zhang, Q. et al. Organic anion transporter OAT1 undergoes constitutive and protein kinase C-regulated trafficking through a dynamin-and clathrin-dependent pathway. J. Biol. Chem. 283, 32570-32579 (2008).
210. Chow, E. C., Sun, H., Khan, A. A., Groothuis, G. M. & Pang, K. S. Effects of 1α, 25-dihydroxyvitamin D3 on transporters and enzymes of the rat intestine and kidney in vivo. Biopharm. Drug Dispos. 31, 91-108 (2010).
211. Physicians' Desk Reference (Thomson PDR, 2014).
212. Zheng, W. H. et al. Evolutionary relationships of ATP-Binding Cassette (ABC) uptake porters. BMC Microbiol. 13, 98 (2013).
213. Lorca, G. L. et al. Transport capabilities of eleven gram-positive bacteria: comparative genomic analyses. Biochim. Biophys. Acta 1768, 1342-1366 (2007).
214. Zhang, X. et al. Twelve transmembrane helices form the functional core of mammalian MATE1 (multidrug and toxin extruder 1) protein. J. Biol. Chem. 287, 27971-27982 (2012).
215. Eraly, S. A., Hamilton, B. A. & Nigam, S. K. Organic anion and cation transporters occur in pairs of similar and similarly expressed genes. Biochem. Biophys. Res. Commun. 300, 333-342 (2003).
216. Wu, W., Baker, M. E., Eraly, S. A., Bush, K. T. & Nigam, S. K. Analysis of a large cluster of SLC22 transporter genes, including novel USTs, reveals species-specific amplification of subsets of family members. Physiol. Genom. 38, 116-124 (2009).
217. Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996-1006 (2002).
218. Konieczna, A. et al. Differential expression of ABC transporters (MDR1, MRP1, BCRP) in developing human embryos. J. Mol. Histol 42, 567-574 (2011).
219. Ricardo, S. & Lehmann, R. An ABC transporter controls export of a Drosophila germ cell attractant. Science 323, 943-946 (2009).
220. Eraly, S. A., Monte, J. C. & Nigam, S. K. Novel slc22 transporter homologs in fly, worm, and human clarify the phylogeny of organic anion and cation transporters. Physiol. Genom. 18, 12-24 (2004).
221. Strader, L. C. & Bartel, B. Transport and metabolism of the endogenous auxin precursor indole-3-butyric acid. Mol. Plant 4, 477-486 (2011).
222. Good, J. R. et al. TagA, a putative serine protease/ABC transporter of Dictyostelium that is required for cell fate determination at the onset of development. Development 130, 2953-2965 (2003).
223. Mao, Q., Ganapathy, V. & Unadkat, J. D. in Drug Transporters: Molecular Characterization and Role in Drug Disposition (eds You, G. & Morris, M. E.) 341-354 (John Wiley & Sons, 2014).
224. Funk, R. S., Brown, J. T. & Abdel-Rahman, S. M. Pediatric pharmacokinetics: human development and drug disposition. Pediatr. Clin. North Am. 59, 1001-1016 (2012).
225. Sweet, D. H., Eraly, S. A., Vaughn, D. A., Bush, K. T. & Nigam, S. K. Organic anion and cation transporter expression and function during embryonic kidney development and in organ culture models. Kidney Int. 69, 837-845 (2006).
226. Gallegos, T. F., Martovetsky, G., Kouznetsova, V., Bush, K. T. & Nigam, S. K. Organic anion and cation SLC22 'drug' transporter (Oat1, Oat3, and Oct1) regulation during development and maturation of the kidney proximal tubule. PLoS ONE 7, e40796 (2012).
227. Gao, B., St Pierre, M. V., Stieger, B. & Meier, P. J. Differential expression of bile salt and organic anion transporters in developing rat liver. J. Hepatol. 41, 201-208 (2004).
228. Braunlich, H. Postnatal development of kidney function in rats receiving thyroid hormones. Exp. Clin. Endocrinol. 83, 243-250 (1984).
229. Bush, K. T. et al. in Drug Transporters: Molecular Characterization and Role in Drug Disposition (eds You, G. & Morris, M. E.) 25-42 (John Wiley & Sons, 2014).
230. Nozaki, Y. et al. Species difference in the inhibitory effect of nonsteroidal anti-inflammatory drugs on the uptake of methotrexate by human kidney slices. J. Pharmacol. Exp. Ther. 322, 1162-1170 (2007).
231. Shibayama, Y. et al. Effect of methotrexate treatment on expression levels of multidrug resistance protein 2, breast cancer resistance protein and organic anion transporters Oat1, Oat2 and Oat3 in rats. Cancer Sci. 97, 1260-1266 (2006).
232. Cheng, Y., Vapurcuyan, A., Shahidullah, M., Aleksunes, L. M. & Pelis, R. M. Expression of organic anion transporter 2 in the human kidney and its potential role in the tubular secretion of guanine-containing antiviral drugs. Drug Metab. Dispos. 40, 617-624 (2012).
233. Staud, F., Cerveny, L., Ahmadimoghaddam, D. & Ceckova, M. Multidrug and toxin extrusion proteins (MATE/SLC47); role in pharmacokinetics. Int. J. Biochem. Cell Biol. 45, 2007-2011 (2013).
234. Aslamkhan, A. G. et al. The flounder organic anion transporter fOat has sequence, function, and substrate specificity similarity to both mammalian Oat1 and Oat3. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R1773-R1780 (2006).
235. Cihlar, T. et al. The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Mol. Pharmacol. 56, 570-580 (1999).
236. Mulato, A. S., Ho, E. S. & Cihlar, T. Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1. J. Pharmacol. Exp. Ther. 295, 10-15 (2000).
237. Hsiang, B. et al. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J. Biol. Chem. 274, 37161-37168 (1999).
238. Nakai, D. et al. Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J. Pharmacol. Exp. Ther. 297, 861-867 (2001).
239. Sasaki, M., Suzuki, H., Ito, K., Abe, T. & Sugiyama, Y. Transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and Multidrug resistance-associated protein 2 (MRP2/ABCC2). J. Biol. Chem. 277, 6497-6503 (2002).
240. Nozawa, T., Imai, K., Nezu, J., Tsuji, A. & Tamai, I. Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J. Pharmacol. Exp. Ther. 308, 438-445 (2004).
241. Takeda, M. et al. Evidence for a role of human organic anion transporters in the muscular side effects of HMG-CoA reductase inhibitors. Eur. J. Pharmacol. 483, 133-138 (2004).
242. Hirano, M., Maeda, K., Hayashi, H., Kusuhara, H. & Sugiyama, Y. Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J. Pharmacol. Exp. Ther. 314, 876-882 (2005).
243. Kitamura, S., Maeda, K., Wang, Y. & Sugiyama, Y. Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab. Dispos. 36, 2014-2023 (2008).
244. Keskitalo, J. E. et al. ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin. Pharmacol. Ther. 86, 197-203 (2009).
245. Ho, R. H. et al. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130, 1793-1806 (2006).
246. Ito, S. et al. Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney. J. Pharmacol. Exp. Ther. 340, 393-403 (2012).
247. Kurata, T., Muraki, Y., Mizutani, H., Iwamoto, T. & Okuda, M. Elevated systemic elimination of cimetidine in rats with acute biliary obstruction: the role of renal organic cation transporter OCT2. Drug Metab. Pharmacokinet. 25, 328-334 (2010).
248. Ohta, K. Y., Inoue, K., Yasujima, T., Ishimaru, M. & Yuasa, H. Functional characteristics of two human MATE transporters: kinetics of cimetidine transport and profiles of inhibition by various compounds. J. Pharm. Pharm. Sci. 12, 388-396 (2009).
249. Tsuda, M. et al. Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J. Pharmacol. Exp. Ther. 329, 185-191 (2009).
250. Tsuda, M. et al. Targeted disruption of the multidrug and toxin extrusion 1 (Mate1) gene in mice reduces renal secretion of metformin. Mol. Pharmacol. 75, 1280-1286 (2009).
251. Tzvetkov, M. V. et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin. Pharmacol. Ther. 86, 299-306 (2009).
252. Ahmadimoghaddam, D. & Staud, F. Transfer of metformin across the rat placenta is mediated by organic cation transporter 3 (OCT3/SLC22A3) and multidrug and toxin extrusion 1 (MATE1/SLC47A1) protein. Reprod. Toxicol. 39, 17-22 (2013).
253. Filipski, K. K., Mathijssen, R. H., Mikkelsen, T. S., Schinkel, A. H., & Sparreboom, A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin. Pharmacol. Ther. 86, 396-402 (2009).
254. More, S. S. et al. Organic cation transporters modulate the uptake and cytotoxicity of picoplatin, a third-generation platinum analogue. Mol. Cancer Ther. 9, 1058-1069 (2010).
255. Ho, G. T. et al. ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach. Hum. Mol. Genet. 15, 797-805 (2006).
256. Krupoves, A. et al. Associations between ABCB1/MDR1 gene polymorphisms and Crohn's disease: a gene-wide study in a pediatric population. Inflamm. Bowel Dis. 15, 900-908 (2009).