Polymorphisms of the drug transporters ABCB1, ABCG2, ABCC2 and ABCC3 and their impact on drug bioavailability and clinical relevance

Expert Opinion on Drug Metabolism and Toxicology

Volumn 10, Issue 10, 2014, Pages 1337-1354

  Bruhn, Oliver ^a   Cascorbi, Ingolf ^a  

^a UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

Author keywords

ATP binding cassette transporters; Drug response; Efflux transporter; Multidrug resistance; Pharmacogenetics; Pharmacokinetics; Transmembranal transport

Indexed keywords

ABC TRANSPORTER; ACID; ANTINEOPLASTIC AGENT; ATAZANAVIR; BREAST CANCER RESISTANCE PROTEIN; CYCLOSPORIN; DIGOXIN; DOXORUBICIN; ERLOTINIB; ETOPOSIDE; FEXOFENADINE; GEFITINIB; IMATINIB; INDINAVIR; LOPERAMIDE; LOPINAVIR; METHADONE; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 2; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 3; MULTIDRUG RESISTANCE PROTEIN 1; NELFINAVIR; OXYCODONE; PACLITAXEL; RAPAMYCIN; TACROLIMUS; TALINOLOL; UNINDEXED DRUG; VINBLASTINE; VINCRISTINE; XENOBIOTIC AGENT; ABCB1 PROTEIN, HUMAN; ABCG2 PROTEIN, HUMAN; BIOLOGICAL MARKER; MULTIDRUG RESISTANCE PROTEIN; MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2; MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 3; TUMOR PROTEIN;

AMINO ACID SUBSTITUTION; COHORT ANALYSIS; DRUG BIOAVAILABILITY; DRUG RESPONSE; EXON; GENE; GENETIC POLYMORPHISM; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; HUMAN; META ANALYSIS (TOPIC); NONHUMAN; PHARMACOGENETICS; PHARMACOKINETICS; REGULATORY MECHANISM; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; STUDY DESIGN; SYSTEMATIC REVIEW; TRANSCRIPTION REGULATION; TREATMENT OUTCOME; TREATMENT RESPONSE; ANIMAL; BIOAVAILABILITY; GENETICS; METABOLISM; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; ATP-BINDING CASSETTE TRANSPORTERS; BIOLOGICAL AVAILABILITY; BIOLOGICAL MARKERS; BIOLOGICAL TRANSPORT; GENETIC VARIATION; HUMANS; MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS; NEOPLASM PROTEINS; P-GLYCOPROTEINS; POLYMORPHISM, GENETIC;

EID: 84907178152     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2014.952630     Document Type: Review

References (186)

1. Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding cassette (ABC) transporter family. Hum Genomics 2009;3:281-90
2. Human ATP-Binding Cassette Transporters. The Nutrition MaGG, Wageningen University, The Netherlands. 2006. Available from: Http://nutrigene.4t.com/humanabc.htm
3. Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem 2002;71:537-92
4. Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 2001;11:1156-66
5. Cascorbi I, Haenisch S. Pharmacogenetics of ATP-binding cassette transporters and clinical implications. Methods Mol Biol 2010;596:95-121
6. Cascorbi I. Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther 2006;112:457-73
7. Biedler JL, Riehm H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro: Cross-resistance, radioautographic, and cytogenetic studies. Cancer Res 1970;30:1174-84
8. Juranka PF, Zastawny RL, Ling V. P-glycoprotein: Multidrug-resistance and a superfamily of membrane-associated transport proteins. FASEB J 1989;3:2583-92
9. Mealey KL, Bentjen SA, Gay JM, et al. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 2001;11:727-33
10. Schinkel AH, Mayer U, Wagenaar E, et al. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 1997;94:4028-33
11. Bao L, Hazari S, Mehra S, et al. Increased expression of P-glycoprotein and doxorubicin chemoresistance of metastatic breast cancer is regulated by miR-298. Am J Pathol 2012;180:2490-503
12. Ikemura K, Yamamoto M, Miyazaki S, et al. MicroRNA-145 posttranscriptionally regulates the expression and function of P-glycoprotein in intestinal epithelial cells. Mol Pharmacol 2013;83:399-405
13. Zhu H, Wu H, Liu X, et al. Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells. Biochem Pharmacol 2008;76:582-8
14. Canaparo R, Finnstrom N, Serpe L, et al. Expression of CYP3A isoforms and P-glycoprotein in human stomach, jejunum and ileum. Clin Exp Pharmacol Physiol 2007;34:1138-44
15. Zhang Y, Benet LZ. The gut as a barrier to drug absorption: Combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 2001;40:159-68
16. del Moral RG, Olmo A, Aguilar M, et al. P glycoprotein: A new mechanism to control drug-induced nephrotoxicity. Exp Nephrol 1998;6:89-97
17. Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 1995;275:1011-18
18. Loscher W, Klotz U, Zimprich F, et al. The clinical impact of pharmacogenetics on the treatment of epilepsy. Epilepsia 2009;50:1-23
19. Miller DS, Bauer B, Hartz AM. Modulation of P-glycoprotein at the blood-brain barrier: Opportunities to improve central nervous system pharmacotherapy. Pharmacol Rev 2008;60:196-209
20. Chandler B, Detsika M, Khoo SH, et al. Factors impacting the expression of membrane-bound proteins in lymphocytes from HIV-positive subjects. J Antimicrob Chemother 2007;60:685-9
21. Svirnovski AI, Shman TV, Serhiyenka TF, et al. ABCB1 and ABCG2 proteins, their functional activity and gene expression in concert with drug sensitivity of leukemia cells. Hematology( Am Soc Hematol Educ Program) 2009;14:204-12
22. Riordan JR, Deuchars K, Kartner N, et al. Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. Nature 1985;316:817-19
23. Bodor M, Kelly EJ, Ho RJ. Characterization of the human MDR1 gene. AAPS J 2005;7:E1-5
24. Lelong-Rebel IH, Cardarelli CO. Differential phosphorylation patterns of P-glycoprotein reconstituted into a proteoliposome system: Insight into additional unconventional phosphorylation sites. Anticancer Res 2005;25:3925-35
25. NIoH. Pharmacogenomics Knowledge Base (PharmGKB). 2014. Available from: Www.pharmgkb.org
26. NIoH. Pharmacogenetics of Membrane Transporters Database. 2014. Available from: Http://pharmacogenetics. ucsf.edu
27. Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with Pglycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000;97:3473-8
28. Johne A, Kopke K, Gerloff T, et al. Modulation of steady-state kinetics of digoxin by haplotypes of the Pglycoprotein MDR1 gene. Clin Pharmacol Ther 2002;72:584-94
29. Aarnoudse AJ, Dieleman JP, Visser LE, et al. Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration. Pharmacogenet Genomics 2008;18:299-305
30. Sakaeda T, Nakamura T, Horinouchi M, et al. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res 2001;18:1400-4
31. Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A silent polymorphism in the MDR1 gene changes substrate specificity. Science 2007;315:525-8
32. Chowbay B, Li H, David M, et al. Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression. Br J Clin Pharmacol 2005;60:159-71
33. Drescher S, Schaeffeler E, Hitzl M, et al. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 2002;53:526-34
34. Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001;70:189-99
35. Jiang ZP, Wang YR, Xu P, et al. Meta-analysis of the effect of MDR1 C3435T polymorphism on cyclosporine pharmacokinetics. Basic Clin Pharmacol Toxicol 2008;103:433-44
36. Press RR, Ploeger BA, den Hartigh J, et al. Explaining variability in ciclosporin exposure in adult kidney transplant recipients. Eur J Clin Pharmacol 2010;66:579-90
37. Renders L, Frisman M, Ufer M, et al. CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients. Clin Pharmacol Ther 2007;81:228-34
38. Ufer M, Dilger K, Leschhorn L, et al. Influence of CYP3A4, CYP3A5, and ABCB1 genotype and expression on budesonide pharmacokinetics: A possible role of intestinal CYP3A4 expression. Clin Pharmacol Ther 2008;84:43-6
39. Yanagimachi M, Naruto T, Tanoshima R, et al. Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitorrelated neurotoxicity after hematopoietic stem cell transplantation. Clin Transplant 2010;24:855-61
40. Crettol S, Venetz JP, Fontana M, et al. Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients. Pharmacogenet Genomics 2008;18:307-15
41. Colombo S, Soranzo N, Rotger M, et al. Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo. Pharmacogenet Genomics 2005;15:599-608
42. Saitoh A, Capparelli E, Aweeka F, et al. CYP2C19 genetic variants affect nelfinavir pharmacokinetics and virologic response in HIV-1-infected children receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2010;54(3):285-9
43. Solas C, Simon N, Drogoul MP, et al. Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIVinfected patients. Br J Clin Pharmacol 2007;64:353-62
44. Winzer R, Langmann P, Zilly M, et al. No influence of the P-glycoprotein genotype (MDR1 C3435T) on plasma levels of lopinavir and efavirenz during antiretroviral treatment. Eur J Med Res 2003;8:531-4
45. Kim DH, Park JY, Sohn SK, et al. Multidrug resistance-1 gene polymorphisms associated with treatment outcomes in de novo acute myeloid leukemia. Int J Cancer 2006;118:2195-201
46. van der Holt B, van den Heuvel-Eibrink MM, van Schaik RH, et al. ABCB1 gene polymorphisms are not associated with treatment outcome in elderly acute myeloid leukemia patients. Clin Pharmacol Ther 2006;80:427-39
47. Dulucq S, Bouchet S, Turcq B, et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2008;112:2024-7
48. Hur EH, Lee JH, Lee MJ, et al. C3435T polymorphism of the MDR1 gene is not associated with P-glycoprotein function of leukemic blasts and clinical outcome in patients with acute myeloid leukemia. Leuk Res 2008;32:1601-4
49. Buda G, Maggini V, Galimberti S, et al. MDR1 polymorphism influences the outcome of multiple myeloma patients. Br J Haematol 2007;137:454-6
50. Hughes JR. One of the hottest topics in epileptology: ABC proteins. Their inhibition may be the future for patients with intractable seizures. Neurol Res 2008;30:920-5
51. Baltes S, Gastens AM, Fedrowitz M, et al. Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology 2007;52:333-46
52. Siddiqui A, Kerb R, Weale ME, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 2003;348:1442-8
53. Hung CC, Tai JJ, Lin CJ, et al. Complex haplotypic effects of the ABCB1 gene on epilepsy treatment response. Pharmacogenomics 2005;6:411-17
54. Seo T, Ishitsu T, Ueda N, et al. ABCB1 polymorphisms influence the response to antiepileptic drugs in Japanese epilepsy patients. Pharmacogenomics 2006;7:551-61
55. Bournissen FG, Moretti ME, Juurlink DN, et al. Polymorphism of the MDR1/ABCB1 C3435T drugtransporter and resistance to anticonvulsant drugs: A meta-analysis. Epilepsia 2009;50:898-903
56. Haerian BS, Lim KS, Tan CT, et al. Association of ABCB1 gene polymorphisms and their haplotypes with response to antiepileptic drugs: A systematic review and meta-analysis. Pharmacogenomics 2011;12:713-25
57. Cascorbi I. ABC transporters in drugrefractory epilepsy: Limited clinical significance of pharmacogenetics? Clin Pharmacol Ther 2010;87:15-18
58. Lotsch J, Tegeder I, Angst MS, et al. Antinociceptive effects of morphine-6-glucuronide in homozygous MDR1a P-glycoprotein knockout and in wildtype mice in the hotplate test. Life Sci 2000;66:2393-403
59. Skarke C, Jarrar M, Schmidt H, et al. Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics 2003;13:651-60
60. Campa D, Gioia A, Tomei A, et al. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther 2008;83:559-66
61. Lotsch J, von Hentig N, Freynhagen R, et al. Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers. Pharmacogenet Genomics 2009;19:429-36
62. Zwisler ST, Enggaard TP, Noehr-Jensen L, et al. The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes. Fundam Clin Pharmacol 2010;24:517-24
63. Crettol S, Deglon JJ, Besson J, et al. No influence of ABCB1 haplotypes on methadone dosage requirement. Clin Pharmacol Ther 2008;83:668-9
64. Lotsch J, Skarke C, Wieting J, et al. Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther 2006;79:72-89
65. Singh R, Srivastava A, Kapoor R, et al. Do drug transporter (ABCB1) SNPs influence cyclosporine and tacrolimus dose requirements and renal allograft outcome in the posttransplantation period? J Clin Pharmacol 2011;51:603-15
66. Karlsson L, Green H, Zackrisson AL, et al. ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram. Int J Legal Med 2013;127:579-86
67. Schaefer M, Roots I, Gerloff T. In-vitro transport characteristics discriminate wild-type ABCB1 (MDR1) from ALA893SER and ALA893THR polymorphisms. Pharmacogenet Genomics 2006;16:855-61
68. Ishikawa T, Sakurai A, Kanamori Y, et al. High-speed screening of human ATP-binding cassette transporter function and genetic polymorphisms: New strategies in pharmacogenomics. Methods Enzymol 2005;400:485-510
69. Plasschaert SL, Groninger E, Boezen M, et al. Influence of functional polymorphisms of the MDR1 gene on vincristine pharmacokinetics in childhood acute lymphoblastic leukemia. Clin Pharmacol Ther 2004;76:220-9
70. Siegmund W, Ludwig K, Giessmann T, et al. The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther 2002;72:572-83
71. Ross JR, Riley J, Taegetmeyer AB, et al. Genetic variation and response to morphine in cancer patients: Catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects. Cancer 2008;112:1390-403
72. Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 2001;69:169-74
73. Levran O, O'Hara K, Peles E, et al. ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence. Hum Mol Genet 2008;17:2219-27
74. Crouthamel MH, Wu D, Yang Z, et al. A novel MDR1 G1199T variant alters drug resistance and efflux transport activity of P-glycoprotein in recombinant HEK cells. J Pharm Sci 2006;95:2767-77
75. Yang Z, Wu D, Bui T, et al. A novel human multidrug resistance gene MDR1 variant G571A (G191R) modulates cancer drug resistance and efflux transport. J Pharmacol Exp Ther 2008;327:474-81
76. Jeong H, Herskowitz I, Kroetz DL, et al. Function-altering SNPs in the human multidrug transporter gene ABCB1 identified using a Saccharomyces-based assay. PLoS Genet 2007;3:e39
77. Gow JM, Hodges LM, Chinn LW, et al. Substrate-dependent effects of human ABCB1 coding polymorphisms. J Pharmacol Exp Ther 2008;325:435-42
78. Doyle LA, Yang W, Abruzzo LV, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 1998;95:15665-70
79. Lepper ER, Nooter K, Verweij J, et al. Mechanisms of resistance to anticancer drugs: The role of the polymorphic ABC transporters ABCB1 and ABCG2. Pharmacogenomics 2005;6:115-38
80. Bailey-Dell KJ, Hassel B, Doyle LA, et al. Promoter characterization and genomic organization of the human breast cancer resistance protein (ATPbinding cassette transporter G2) gene. Biochim Biophys Acta 2001;1520:234-41
81. Maliepaard M, Scheffer GL, Faneyte IF, et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res 2001;61:3458-64
82. Woodward OM, Kottgen A, Coresh J, et al. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci USA 2009;106:10338-42
83. van Herwaarden AE, Wagenaar E, Merino G, et al. Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk. Mol Cell Biol 2007;27:1247-53
84. Misaghian N, Ligresti G, Steelman LS, et al. Targeting the leukemic stem cell: The Holy Grail of leukemia therapy. Leukemia 2009;23:25-42
85. Ono M, Maruyama T, Masuda H, et al. Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells. Proc Natl Acad Sci USA 2007;104:18700-5
86. Uezumi A, Ojima K, Fukada S, et al. Functional heterogeneity of side population cells in skeletal muscle. Biochem Biophys Res Commun 2006;341:864-73
87. Oh H, Chi X, Bradfute SB, et al. Cardiac muscle plasticity in adult and embryo by heart-derived progenitor cells. Ann N Y Acad Sci 2004;1015:182-9
88. Lechner A, Leech CA, Abraham EJ, et al. Nestin-positive progenitor cells derived from adult human pancreatic islets of Langerhans contain side population (SP) cells defined by expression of the ABCG2 (BCRP1) ATP-binding cassette transporter. Biochem Biophys Res Commun 2002;293:670-4
89. Sparreboom A, Gelderblom H, Marsh S, et al. Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype. Clin Pharmacol Ther 2004;76:38-44
90. Sparreboom A, Loos WJ, Burger H, et al. Effect of ABCG2 genotype on the oral bioavailability of topotecan. Cancer Biol Ther 2005;4:650-8
91. de Jong FA, Marsh S, Mathijssen RH, et al. ABCG2 pharmacogenetics: Ethnic differences in allele frequency and assessment of influence on irinotecan disposition. Clin Cancer Res 2004;10:5889-94
92. Zhou Q, Sparreboom A, Tan EH, et al. Pharmacogenetic profiling across the irinotecan pathway in Asian patients with cancer. Br J Clin Pharmacol 2005;59:415-24
93. Han JY, Lim HS, Yoo YK, et al. Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecanpharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. Cancer 2007;110:138-47
94. Sai K, Saito Y, Maekawa K, et al. Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients. Cancer Chemother Pharmacol 2010;66:95-105
95. Chew SC, Singh O, Chen X, et al. The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of docetaxel in nasopharyngeal carcinoma patients. Cancer Chemother Pharmacol 2011;67:1471-8
96. Lal S, Wong ZW, Sandanaraj E, et al. Influence of ABCB1 and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients. Cancer Sci 2008;99:816-23
97. Warren RB, Smith RL, Campalani E, et al. Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J Invest Dermatol 2008;128:1925-9
98. Dohse M, Scharenberg C, Shukla S, et al. Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab Dispos 2010;38:1371-80
99. Gardner ER, Burger H, van Schaik RH, et al. Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther 2006;80:192-201
100. Raymond E, Brandes AA, Dittrich C, et al. Phase II study of imatinib in patients with recurrent gliomas of various histologies: A European Organisation for Research and Treatment of Cancer Brain Tumor Group Study. J Clin Oncol 2008;26:4659-65
101. Petain A, Kattygnarath D, Azard J, et al. Population pharmacokinetics and pharmacogenetics of imatinib in children and adults. Clin Cancer Res 2008;14:7102-9
102. Takahashi N, Miura M, Scott SA, et al. Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. J Hum Genet 2010;55:731-7
103. Rudin CM, Liu W, Desai A, et al. Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol 2008;26:1119-27
104. Thomas F, Rochaix P, White-Koning M, et al. Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma. Eur J Cancer 2009;45:2316-23
105. Elmeliegy MA, Carcaboso AM, Tagen M, et al. Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation. Clin Cancer Res 2011;17:89-99
106. Li J, Cusatis G, Brahmer J, et al. Association of variant ABCG2 and the pharmacokinetics of epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients. Cancer Biol Ther 2007;6:432-8
107. Akasaka K, Kaburagi T, Yasuda S, et al. Impact of functional ABCG2 polymorphisms on the adverse effects of gefitinib in Japanese patients with non-small-cell lung cancer. Cancer Chemother Pharmacol 2010;66:691-8
108. Lemos C, Giovannetti E, Zucali PA, et al. Impact of ABCG2 polymorphisms on the clinical outcome and toxicity of gefitinib in non-small-cell lung cancer patients. Pharmacogenomics 2011;12:159-70
109. Zhang W, Yu BN, He YJ, et al. Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta 2006;373:99-103
110. Keskitalo JE, Zolk O, Fromm MF, et al. ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 2009;86:197-203
111. Bailey KM, Romaine SP, Jackson BM, et al. Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: The GEOSTAT-1 Study. Circ Cardiovasc Genet 2010;3:276-85
112. Tomlinson B, Hu M, Lee VW, et al. ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther 2010;87:558-62
113. Keskitalo JE, Pasanen MK, Neuvonen PJ, et al. Different effects of the ABCG2 c.421C>A SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin. Pharmacogenomics 2009;10:1617-24
114. Ieiri I, Suwannakul S, Maeda K, et al. SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 2007;82:541-7
115. Kim HS, Sunwoo YE, Ryu JY, et al. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Br J Clin Pharmacol 2007;64:645-54
116. Adkison KK, Vaidya SS, Lee DY, et al. The ABCG2 C421A polymorphism does not affect oral nitrofurantoin pharmacokinetics in healthy Chinese male subjects. Br J Clin Pharmacol 2008;66:233-9
117. Fukao M, Ishida K, Sakamoto T, et al. Effect of genetic polymorphisms of SLC28A1, ABCG2, and ABCC4 on bioavailability of mizoribine in healthy Japanese males. Drug Metab Pharmacokinet 2011;26:538-43
118. Adkison KK, Vaidya SS, Lee DY, et al. Oral sulfasalazine as a clinical BCRP probe substrate: Pharmacokinetic effects of genetic variation (C421A) and pantoprazole coadministration. J Pharm Sci 2010;99:1046-62
119. Urquhart BL, Ware JA, Tirona RG, et al. Breast cancer resistance protein( ABCG2) and drug disposition: Intestinal expression, polymorphisms and sulfasalazine as an in vivo probe. Pharmacogenet Genomics 2008;18:439-48
120. Kim DH, Sriharsha L, Xu W, et al. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res 2009;15:4750-8
121. van der Veldt AA, Eechoute K, Gelderblom H, et al. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res 2011;17:620-9
122. Kim IS, Kim HG, Kim DC, et al. ABCG2 Q141K polymorphism is associated with chemotherapy-induced diarrhea in patients with diffuse large Bcell lymphoma who received frontline rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone chemotherapy. Cancer Sci 2008;99:2496-501
123. Matsuo H, Takada T, Ichida K, et al. Common defects of ABCG2, a highcapacity urate exporter, cause gout: A function-based genetic analysis in a Japanese population. Sci Transl Med 2009;1:5ra11
124. Yoshioka S, Katayama K, Okawa C, et al. The identification of two germ-line mutations in the human breast cancer resistance protein gene that result in the expression of a low/non-functional protein. Pharm Res 2007;24:1108-17
125. Tamura A, Watanabe M, Saito H, et al. Functional validation of the genetic polymorphisms of human ATP-binding cassette (ABC) transporter ABCG2: Identification of alleles that are defective in porphyrin transport. Mol Pharmacol 2006;70:287-96
126. van Erp NP, Eechoute K, van der Veldt AA, et al. Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol 2009;27:4406-12
127. Vethanayagam RR, Wang H, Gupta A, et al. Functional analysis of the human variants of breast cancer resistance protein: I206L, N590Y, and D620N. Drug Metab Dispos 2005;33:697-705
128. Poonkuzhali B, Lamba J, Strom S, et al. Association of breast cancer resistance protein/ABCG2 phenotypes and novel promoter and intron 1 single nucleotide polymorphisms. Drug Metab Dispos 2008;36:780-95
129. Ni W, Ji J, Dai Z, et al. Flavopiridol pharmacogenetics: Clinical and functional evidence for the role of SLCO1B1/OATP1B1 in flavopiridol disposition. PLoS One 2010;5:e13792
130. Rosenberg MF, Oleschuk CJ, Wu P, et al. Structure of a human multidrug transporter in an inward-facing conformation. J Struct Biol 2010;170:540-7
131. Aronica E, Gorter JA, Ramkema M, et al. Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with mesial temporal lobe epilepsy. Epilepsia 2004;45:441-51
132. Hoque MT, Conseil G, Cole SP. Involvement of NHERF1 in apical membrane localization of MRP4 in polarized kidney cells. Biochem Biophys Res Commun 2009;379:60-4
133. Keppler D, Leier I, Jedlitschky G, et al. The function of the multidrug resistance proteins (MRP and cMRP) in drug conjugate transport and hepatobiliary excretion. Adv Enzyme Regul 1996;36:17-29
134. Konig J, Rost D, Cui Y, et al. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology 1999;29:1156-63
135. Borst P, de Wolf C, van de Wetering K. Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch 2007;453:661-73
136. Nies AT, Keppler D. The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch 2007;453:643-59
137. Dubin IN, Johnson FB. Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases. Medicine (Baltimore) 1954;33:155-97
138. Lee JH, Chen HL, Ni YH, et al. Neonatal Dubin-Johnson syndrome: Long-term follow-up and MRP2 mutations study. Pediatr Res 2006;59:584-9
139. Paulusma CC, Oude Elferink RP. The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man. J Mol Med (Berl) 1997;75:420-8
140. Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: New insights into molecular mechanisms and consequences. Gastroenterology 2014;146:1625-38
141. Haenisch S, Zimmermann U, Dazert E, et al. Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex. Pharmacogenomics J 2007;7:56-65
142. Laechelt S, Turrini E, Ruehmkorf A, et al. Impact of ABCC2 haplotypes on transcriptional and posttranscriptional gene regulation and function. Pharmacogenomics J 2011;11:25-34
143. Rau T, Erney B, Gores R, et al. High-dose methotrexate in pediatric acute lymphoblastic leukemia: Impact of ABCC2 polymorphisms on plasma concentrations. Clin Pharmacol Ther 2006;80:468-76
144. Levesque E, Benoit-Biancamano MO, Delage R, et al. Pharmacokinetics of mycophenolate mofetil and its glucuronide metabolites in healthy volunteers. Pharmacogenomics 2008;9:869-79
145. Miura M, Satoh S, Inoue K, et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 2007;63:1161-9
146. Baldelli S, Merlini S, Perico N, et al. C- 440T/T-331C polymorphisms in the UGT1A9 gene affect the pharmacokinetics of mycophenolic acid in kidney transplantation. Pharmacogenomics 2007;8:1127-41
147. Zhang WX, Chen B, Jin Z, et al. Influence of uridine diphosphate (UDP)- glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients. Xenobiotica 2008;38:1422-36
148. Naesens M, Kuypers DR, Verbeke K, et al. Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 2006;82:1074-84
149. Innocenti F, Kroetz DL, Schuetz E, et al. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J Clin Oncol 2009;27:2604-14
150. Miura M, Satoh S, Inoue K, et al. Telmisartan pharmacokinetics in Japanese renal transplant recipients. Clin Chim Acta 2009;399:83-7
151. Choi JH, Ahn BM, Yi J, et al. MRP2 haplotypes confer differential susceptibility to toxic liver injury. Pharmacogenet Genomics 2007;17:403-15
152. Daly AK, Aithal GP, Leathart JB, et al. Genetic susceptibility to diclofenacinduced hepatotoxicity: Contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 2007;132:272-81
153. Haenisch S, May K, Wegner D, et al. Influence of genetic polymorphisms on intestinal expression and rifampicin-type induction of ABCC2 and on bioavailability of talinolol. Pharmacogenet Genomics 2008;18:357-65
154. Meyer zu Schwabedissen HE, Jedlitschky G, Gratz M, et al. Variable expression of MRP2 (ABCC2) in human placenta: Influence of gestational age and cellular differentiation. Drug Metab Dispos 2005;33:896-904
155. Ogasawara K, Chitnis SD, Gohh RY, et al. Multidrug resistance-associated protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of tacrolimus in kidney transplant recipients. Clin Pharmacokinet 2013;52:751-62
156. Becker ML, Elens LL, Visser LE, et al. Genetic variation in the ABCC2 gene is associated with dose decreases or switches to other cholesterol-lowering drugs during simvastatin and atorvastatin therapy. Pharmacogenomics J 2013;13:251-6
157. 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
158. Hirouchi M, Suzuki H, Itoda M, et al. Characterization of the cellular localization, expression level, and function of SNP variants of MRP2/ABCC2. Pharm Res 2004;21:742-8
159. Ufer M, Mosyagin I, Muhle H, et al. Non-response to antiepileptic pharmacotherapy is associated with the ABCC2 -24C>T polymorphism in young and adult patients with epilepsy. Pharmacogenet Genomics 2009;19:353-62
160. Ufer M, von Stulpnagel C, Muhle H, et al. Impact of ABCC2 genotype on antiepileptic drug response in Caucasian patients with childhood epilepsy. Pharmacogenet Genomics 2011;21:624-30
161. Kim WJ, Lee JH, Yi J, et al. A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy. Pharmacogenet Genomics 2010;20:249-56
162. Subenthiran S, Abdullah NR, Joseph JP, et al. Linkage disequilibrium between polymorphisms of ABCB1 and ABCC2 to predict the treatment outcome of Malaysians with complex partial seizures on treatment with carbamazepine mono-therapy at the Kuala Lumpur Hospital. PLoS One 2013;8:e64827
163. Werk AN, Bruckmueller H, Haenisch S, et al. Genetic variants may play an important role in mRNA-miRNA interaction: Evidence for haplotypedependent downregulation of ABCC2( MRP2) by miRNA-379. Pharmacogenet Genomics 2014;24:283-91
164. Saito S, Iida A, Sekine A, et al. Identification of 779 genetic variations in eight genes encoding members of the ATP-binding cassette, subfamily C( ABCC/MRP/CFTR. J Hum Genet 2002;47:147-71
165. Fukushima-Uesaka H, Saito Y, Maekawa K, et al. Genetic variations of the ABC transporter gene ABCC3 in a Japanese population. Drug Metab Pharmacokinet 2007;22:129-35
166. Lang T, Hitzl M, Burk O, et al. Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver. Pharmacogenetics 2004;14:155-64
167. Steinbach D, Wittig S, Cario G, et al. The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype. Blood 2003;102:4493-8
168. Steinbach D, Lengemann J, Voigt A, et al. Response to chemotherapy and expression of the genes encoding the multidrug resistance-associated proteins MRP2, MRP3, MRP4, MRP5, and SMRP in childhood acute myeloid leukemia. Clin Cancer Res 2003;9:1083-6
169. Doerfel C, Rump A, Sauerbrey A, et al. In acute leukemia, the polymorphism -211C>T in the promoter region of the multidrug resistance-associated protein 3( MRP3) does not determine the expression level of the gene. Pharmacogenet Genomics 2006;16:149-50
170. Ansari M, Sauty G, Labuda M, et al. Polymorphism in multidrug resistanceassociated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia. Pharmacogenomics J 2012;12:386-94
171. Muller P, Asher N, Heled M, et al. Polymorphisms in transporter and phase II metabolism genes as potential modifiers of the predisposition to and treatment outcome of de novo acute myeloid leukemia in Israeli ethnic groups. Leuk Res 2008;32:919-29
172. Muller PJ, Dally H, Klappenecker CN, et al. Polymorphisms in ABCG2, ABCC3 and CNT1 genes and their possible impact on chemotherapy outcome of lung cancer patients. Int J Cancer 2009;124:1669-74
173. Lee YM, Cui Y, Konig J, et al. Identification and functional characterization of the natural variant MRP3-Arg1297His of human multidrug resistance protein 3 (MRP3/ABCC3). Pharmacogenetics 2004;14:213-23
174. Kobayashi K, Ito K, Takada T, et al. Functional analysis of nonsynonymous single nucleotide polymorphism type ATP-binding cassette transmembrane transporter subfamily C member 3. Pharmacogenet Genomics 2008;18:823-33
175. Zou JJ, Fan HW, Chen SL, et al. Efffect of the ABCC3 -211C/T polymorphism on clopidogrel responsiveness in patients with percutaneous coronary intervention. Clin Exp Pharmacol Physiol 2013;40:504-9
176. O'Brien C, Cavet G, Pandita A, et al. Functional genomics identifies ABCC3 as a mediator of taxane resistance in HER2- amplified breast cancer. Cancer Res 2008;68:5380-9
177. Haenisch S, Werk AN, Cascorbi I. MicroRNAs and their relevance to ABC transporters. Br J Clin Pharmacol 2014;77:587-96
178. Ebid AH, Ahmed MM, Mohammed SA. Therapeutic drug monitoring and clinical outcomes in epileptic Egyptian patients: A gene polymorphism perspective study. Ther Drug Monit 2007;29:305-12
179. Seedhouse CH, Grundy M, White P, et al. Sequential influences of leukemiaspecific and genetic factors on Pglycoprotein expression in blasts from 817 patients entered into the National Cancer Research Network acute myeloid leukemia 14 and 15 trials. Clin Cancer Res 2007;13:7059-66
180. Soranzo N, Cavalleri GL, Weale ME, et al. Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene. Genome Res 2004;14:1333-44
181. Zimprich F, Sunder-Plassmann R, Stogmann E, et al. Association of an ABCB1 gene haplotype with pharmacoresistance in temporal lobe epilepsy. Neurology 2004;63:1087-9
182. Imai Y, Nakane M, Kage K, et al. C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. Mol Cancer Ther 2002;1:611-16
183. Hoblinger A, Grunhage F, Sauerbruch T, et al. Association of the c.3972C>T variant of the multidrug resistanceassociated protein 2 Gene (MRP2/ABCC2) with susceptibility to bile duct cancer. Digestion 2009;80:36-9
184. Elens L, Yombi JC, Lison D, et al. Association between ABCC2 polymorphism and lopinavir accumulation in peripheral blood mononuclear cells of HIV-infected patients. Pharmacogenomics 2009;10:1589-97
185. Aller SG, Yu J, Ward A, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 2009;323:1718-22
186. Wolf SJ, Bachtiar M, Wang J, et al. An update on ABCB1 pharmacogenetics: Insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics. Pharmacogenomics J 2011;11:315-25