Abstract
This chapter provides a review of the pharmacogenetics of membrane transporters, including ABC transporters and OATPs. Membrane transporters are heavily involved in drug disposition, by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have a significant effect on the absorption, distribution, metabolism, excretion, and activity of compounds. Although few drug transporter polymorphisms have transitioned from the bench to the bedside, this chapter discusses clinical development of transporter pharmacogenetic markers. Finally, development of SLCO1B1 genotyping to avoid statin induced adverse drug reactions is discussed as a model case for transporter pharmacogenetics clinical development.
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Konig J, Muller F, Fromm MF (2013) Transporters and drug–drug interactions: important determinants of drug disposition and effects. Pharmacol Rev 65:944–966
DeGorter MK, Xia CQ, Yang JJ, Kim RB (2012) Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol 52:249–273
Silverton L, Dean M, Moitra K (2011) Variation and evolution of the ABC transporter genes ABCB1, ABCC1, ABCG2, ABCG5 and ABCG8: implication for pharmacogenetics and disease. Drug Metabol Drug Interact 26:169–179
Vasiliou V, Vasiliou K, Nebert DW (2009) Human ATP-binding cassette (ABC) transporter family. Hum Genomics 3:281–290
Borst P, Evers R, Kool M, Wijnholds J (2000) A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 92:1295–1302
Franke RM, Gardner ER, Sparreboom A (2010) Pharmacogenetics of drug transporters. Curr Pharm Des 16:220–230
Lepper ER, Nooter K, Verweij J, Acharya MR, Figg WD, Sparreboom A (2005) Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2. Pharmacogenomics 6:115–138
Fojo AT, Shen DW, Mickley LA, Pastan I, Gottesman MM (1987) Intrinsic drug resistance in human kidney cancer is associated with expression of a human multidrug-resistance gene. J Clin Oncol 5:1922–1927
Maliepaard M, Scheffer GL, Faneyte IF, van Gastelen MA, Pijnenborg AC, Schinkel AH, van De Vijver MJ, Scheper RJ, Schellens JH (2001) Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res 61:3458–3464
Schellens JH, Malingre MM, Kruijtzer CM, Bardelmeijer HA, van Tellingen O, Schinkel AH, Beijnen JH (2000) Modulation of oral bioavailability of anticancer drugs: from mouse to man. Eur J Pharm Sci 12:103–110
Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, van der Valk MA, Voordouw AC, Spits H, van Tellingen O, Zijlmans JM, Fibbe WE, Borst P (1997) Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci U S A 94:4028–4033
Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A 84:7735–7738
Gottesman MM, Ambudkar SV (2001) Overview: ABC transporters and human disease. J Bioenerg Biomembr 33:453–458
Xiao JJ, Foraker AB, Swaan PW, Liu S, Huang Y, Dai Z, Chen J, Sadee W, Byrd J, Marcucci G, Chan KK (2005) Efflux of depsipeptide FK228 (FR901228, NSC-630176) is mediated by P-glycoprotein and multidrug resistance-associated protein 1. J Pharmacol Exp Ther 313:268–276
Chaudhary PM, Roninson IB (1991) Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66:85–94
Fromm MF (2004) Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol Sci 25:423–429
Leslie EM, Deeley RG, Cole SP (2005) Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 204:216–237
Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC, Piwnica-Worms D (1999) Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A 96:3900–3905
Wijnholds J, deLange EC, Scheffer GL, van den Berg DJ, Mol CA, van der Valk M, Schinkel AH, Scheper RJ, Breimer DD, Borst P (2000) Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. J Clin Invest 105:279–285
Robey RW, To KK, Polgar O, Dohse M, Fetsch P, Dean M, Bates SE (2009) ABCG2: a perspective. Adv Drug Deliv Rev 61:3–13
Borst P, Evers R, Kool M, Wijnholds J (1999) The multidrug resistance protein family. Biochim Biophys Acta 1461:347–357
Hill CR, Jamieson D, Thomas HD, Brown CD, Boddy AV, Veal GJ (2013) Characterisation of the roles of ABCB1, ABCC1, ABCC2 and ABCG2 in the transport and pharmacokinetics of actinomycin D in vitro and in vivo. Biochem Pharmacol 85:29–37
Cascorbi I (2006) Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther 112:457–473
Sissung TM, Troutman SM, Campbell TJ, Pressler HM, Sung H, Bates SE, Figg WD (2012) Transporter pharmacogenetics: transporter polymorphisms affect normal physiology, diseases, and pharmacotherapy. Discov Med 13:19–34
Deeley RG, Cole SP (2006) Substrate recognition and transport by multidrug resistance protein 1 (ABCC1). FEBS Lett 580:1103–1111
Ho RH, Kim RB (2005) Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther 78:260–277
Niemi M, Pasanen MK, Neuvonen PJ (2011) Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 63:157–181
Smith NF, Figg WD, Sparreboom A (2005) Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination. Expert Opin Drug Metab Toxicol 1:429–445
Svoboda M, Riha J, Wlcek K, Jaeger W, Thalhammer T (2011) Organic anion transporting polypeptides (OATPs): regulation of expression and function. Curr Drug Metab 12:139–153
Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R (2008) SLCO1B1 variants and statin-induced myopathy – a genomewide study. N Engl J Med 359:789–799
Buxhofer-Ausch V, Secky L, Wlcek K, Svoboda M, Kounnis V, Briasoulis E, Tzakos AG, Jaeger W, Thalhammer T (2013) Tumor-specific expression of organic anion-transporting polypeptides: transporters as novel targets for cancer therapy. J Drug Deliv 2013:863539
Obaidat A, Roth M, Hagenbuch B (2012) The expression and function of organic anion transporting polypeptides in normal tissues and in cancer. Annu Rev Pharmacol Toxicol 52:135–151
Pressler H, Sissung TM, Venzon D, Price DK, Figg WD (2011) Expression of OATP family members in hormone-related cancers: potential markers of progression. PLoS One 6:e20372
Sainis I, Fokas D, Vareli K, Tzakos AG, Kounnis V, Briasoulis E (2010) Cyanobacterial cyclopeptides as lead compounds to novel targeted cancer drugs. Mar Drugs 8:629–657
Lee W, Belkhiri A, Lockhart AC, Merchant N, Glaeser H, Harris EI, Washington MK, Brunt EM, Zaika A, Kim RB, El-Rifai W (2008) Overexpression of OATP1B3 confers apoptotic resistance in colon cancer. Cancer Res 68:10315–10323
Narita M, Hatano E, Arizono S, Miyagawa-Hayashino A, Isoda H, Kitamura K, Taura K, Yasuchika K, Nitta T, Ikai I, Uemoto S (2009) Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol 44:793–798
Franke RM, Carducci MA, Rudek MA, Baker SD, Sparreboom A (2010) Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer. J Clin Oncol 28:4562–4567
de Graan AJ, Lancaster CS, Obaidat A, Hagenbuch B, Elens L, Friberg LE, de Bruijn P, Hu S, Gibson AA, Bruun GH, Corydon TJ, Mikkelsen TS, Walker AL, Du G, Loos WJ, van Schaik RH, Baker SD, Mathijssen RH, Sparreboom A (2012) Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel. Clin Cancer Res 18:4433–4440
Sharom FJ (2008) ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 9:105–127
Wolf SJ, Bachtiar M, Wang J, Sim TS, Chong SS, Lee CG (2011) 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 11:315–325
Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM (2007) A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528
Longo R, D'Andrea M, Sarmiento R, Gasparini G (2010) Pharmacogenetics in breast cancer: focus on hormone therapy, taxanes, trastuzumab and bevacizumab. Expert Opin Investig Drugs 19(Suppl 1):S41–S50
Sissung TM, Baum CE, Kirkland CT, Gao R, Gardner ER, Figg WD (2010) Pharmacogenetics of membrane transporters: an update on current approaches. Mol Biotechnol 44:152–167
Meissner K, Sperker B, Karsten C, Zu Schwabedissen HM, Seeland U, Bohm M, Bien S, Dazert P, Kunert-Keil C, Vogelgesang S, Warzok R, Siegmund W, Cascorbi I, Wendt M, Kroemer HK (2002) Expression and localization of P-glycoprotein in human heart: effects of cardiomyopathy. J Histochem Cytochem 50:1351–1356
Kurata Y, Ieiri I, Kimura M, Morita T, Irie S, Urae A, Ohdo S, Ohtani H, Sawada Y, Higuchi S, Otsubo K (2002) Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 72:209–219
Tanabe M, Ieiri I, Nagata N, Inoue K, Ito S, Kanamori Y, Takahashi M, Kurata Y, Kigawa J, Higuchi S, Terakawa N, Otsubo K (2001) Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 297:1137–1143
Yi SY, Hong KS, Lim HS, Chung JY, Oh DS, Kim JR, Jung HR, Cho JY, Yu KS, Jang IJ, Shin SG (2004) A variant 2677A allele of the MDR1 gene affects fexofenadine disposition. Clin Pharmacol Ther 76:418–427
Sun J, He ZG, Cheng G, Wang SJ, Hao XH, Zou MJ (2004) Multidrug resistance P-glycoprotein: crucial significance in drug disposition and interaction. Med Sci Monit 10:RA5–RA14
Tsai CJ, Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM, Nussinov R (2008) Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima. J Mol Biol 383:281–291
Tamura A, Wakabayashi K, Onishi Y, Takeda M, Ikegami Y, Sawada S, Tsuji M, Matsuda Y, Ishikawa T (2007) Re-evaluation and functional classification of non-synonymous single nucleotide polymorphisms of the human ATP-binding cassette transporter ABCG2. Cancer Sci 98:231–239
Mizuarai S, Aozasa N, Kotani H (2004) Single nucleotide polymorphisms result in impaired membrane localization and reduced atpase activity in multidrug transporter ABCG2. Int J Cancer 109:238–246
Erdem L, Giovannetti E, Leon LG, Honeywell R, Peters GJ (2012) Polymorphisms to predict outcome to the tyrosine kinase inhibitors gefitinib, erlotinib, sorafenib and sunitinib. Curr Top Med Chem 12:1649–1659
de Jong FA, Marsh S, Mathijssen RH, King C, Verweij J, Sparreboom A, McLeod HL (2004) ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition. Clin Cancer Res 10:5889–5894
Generaux GT, Bonomo FM, Johnson M, Doan KM (2011) Impact of SLCO1B1 (OATP1B1) and ABCG2 (BCRP) genetic polymorphisms and inhibition on LDL-C lowering and myopathy of statins. Xenobiotica 41:639–651
Imai Y, Nakane M, Kage K, Tsukahara S, Ishikawa E, Tsuruo T, Miki Y, Sugimoto Y (2002) 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 1:611–616
Kondo C, Suzuki H, Itoda M, Ozawa S, Sawada J, Kobayashi D, Ieiri I, Mine K, Ohtsubo K, Sugiyama Y (2004) Functional analysis of SNPs variants of BCRP/ABCG2. Pharm Res 21:1895–1903
Allen JD, Jackson SC, Schinkel AH (2002) A mutation hot spot in the Bcrp1 (Abcg2) multidrug transporter in mouse cell lines selected for Doxorubicin resistance. Cancer Res 62:2294–2299
Honjo Y, Hrycyna CA, Yan QW, Medina-Perez WY, Robey RW, van de Laar A, Litman T, Dean M, Bates SE (2001) Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells. Cancer Res 61:6635–6639
Robey RW, Honjo Y, Morisaki K, Nadjem TA, Runge S, Risbood M, Poruchynsky MS, Bates SE (2003) Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity. Br J Cancer 89:1971–1978
Robey RW, Steadman K, Polgar O, Morisaki K, Blayney M, Mistry P, Bates SE (2004) Pheophorbide a is a specific probe for ABCG2 function and inhibition. Cancer Res 64:1242–1246
Letourneau IJ, Deeley RG, Cole SP (2005) Functional characterization of non-synonymous single nucleotide polymorphisms in the gene encoding human multidrug resistance protein 1 (MRP1/ABCC1). Pharmacogenet Genomics 15:647–657
Conseil G, Deeley RG, Cole SP (2005) Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters. Pharmacogenet Genomics 15:523–533
Oselin K, Mrozikiewicz PM, Gaikovitch E, Pahkla R, Roots I (2003) Frequency of MRP1 genetic polymorphisms and their functional significance in Caucasians: detection of a novel mutation G816A in the human MRP1 gene. Eur J Clin Pharmacol 59:347–350
Haufroid V (2011) Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCC2 and their impact on drug disposition. Curr Drug Targets 12:631–646
Gong IY, Kim RB (2013) Impact of genetic variation in OATP transporters to drug disposition and response. Drug Metab Pharmacokinet 28:4–18
Tirona RG, Leake BF, Merino G, Kim RB (2001) Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem 276:35669–35675
Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y, Tsuji A, Yokoi T (2002) Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther 302:804–813
Ho RH, Choi L, Lee W, Mayo G, Schwarz UI, Tirona RG, Bailey DG, Michael Stein C, Kim RB (2007) Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenet Genomics 17:647–656
Mwinyi J, Kopke K, Schaefer M, Roots I, Gerloff T (2008) Comparison of SLCO1B1 sequence variability among German, Turkish, and African populations. Eur J Clin Pharmacol 64:257–266
Letschert K, Keppler D, Konig J (2004) Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8). Pharmacogenetics 14:441–452
Hamada A, Sissung T, Price DK, Danesi R, Chau CH, Sharifi N, Venzon D, Maeda K, Nagao K, Sparreboom A, Mitsuya H, Dahut WL, Figg WD (2008) Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer. Clin Cancer Res 14:3312–3318
Smith NF, Marsh S, Scott-Horton TJ, Hamada A, Mielke S, Mross K, Figg WD, Verweij J, McLeod HL, Sparreboom A (2007) Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics. Clin Pharmacol Ther 81:76–82
Deeken J (2009) The Affymetrix DMET platform and pharmacogenetics in drug development. Curr Opin Mol Ther 11:260–268
Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG (1992) Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258:1650–1654
Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, Weimar W, van Gelder T (2003) Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 74:245–254
Noe B, Hagenbuch B, Stieger B, Meier PJ (1997) Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc Natl Acad Sci U S A 94:10346–10350
Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB (1999) OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 27:866–871
U.S. Food and Drug Administration (2006) Guidance for industry: drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations
Hegedus C, Ozvegy-Laczka C, Apati A, Magocsi M, Nemet K, Orfi L, Keri G, Katona M, Takats Z, Varadi A, Szakacs G, Sarkadi B (2009) Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol 158:1153–1164
International Transporter C, Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236
Bi YA, Kazolias D, Duignan DB (2006) Use of cryopreserved human hepatocytes in sandwich culture to measure hepatobiliary transport. Drug Metab Dispos Biol Fate Chem 34:1658–1665
Barton HA, Lai Y, Goosen TC, Jones HM, El-Kattan AF, Gosset JR, Lin J, Varma MV (2013) Model-based approaches to predict drug-drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond. Expert Opin Drug Metab Toxicol 9:459–472
Hitzl M, Drescher S, van der Kuip H, Schaffeler E, Fischer J, Schwab M, Eichelbaum M, Fromm MF (2001) The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells. Pharmacogenetics 11:293–298
Schaefer M, Roots I, Gerloff T (2005) In vitro transport characteristics discriminate wildtype mdr1 (abcb1) from ala893ser and ala893thr polymorphisms. Eur J Clin Pharmacol 61:718
Ishikawa T, Sakurai A, Kanamori Y, Nagakura M, Hirano H, Takarada Y, Yamada K, Fukushima K, Kitajima M (2005) High-speed screening of human ATP-binding cassette transporter function and genetic polymorphisms: new strategies in pharmacogenomics. Methods Enzymol 400:485–510
Morisaki K, Robey RW, Ozvegy-Laczka C, Honjo Y, Polgar O, Steadman K, Sarkadi B, Bates SE (2005) Single nucleotide polymorphisms modify the transporter activity of ABCG2. Cancer Chemother Pharmacol 56:161–172
Zhang Y, Gupta A, Wang H, Zhou L, Vethanayagam RR, Unadkat JD, Mao Q (2005) BCRP transports dipyridamole and is inhibited by calcium channel blockers. Pharm Res 22:2023–2034
Nakamura Y, Oka M, Soda H, Shiozawa K, Yoshikawa M, Itoh A, Ikegami Y, Tsurutani J, Nakatomi K, Kitazaki T, Doi S, Yoshida H, Kohno S (2005) Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. Cancer Res 65:1541–1546
Iwai M, Suzuki H, Ieiri I, Otsubo K, Sugiyama Y (2004) Functional analysis of single nucleotide polymorphisms of hepatic organic anion transporter OATP1B1 (OATP-C). Pharmacogenetics 14:749–757
Michalski C, Cui Y, Nies AT, Nuessler AK, Neuhaus P, Zanger UM, Klein K, Eichelbaum M, Keppler D, Konig J (2002) A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. J Biol Chem 277:43058–43063
Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I (2005) Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 33:434–439
Tirona RG, Leake BF, Wolkoff AW, Kim RB (2003) Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther 304:223–228
Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97:3473–3478
Song P, Lamba JK, Zhang L, Schuetz E, Shukla N, Meibohm B, Yates CR (2006) G2677T and C3435T genotype and haplotype are associated with hepatic ABCB1 (MDR1) expression. J Clin Pharmacol 46:373–379
Meissner K, Jedlitschky G, Zuschwabedissen MH, Dazert P, Eckel L, Vogelgesang S, Warzok RW, Bohm M, Lehmann C, Wendt M, Cascorbi I, Kroemer HK (2004) Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms. Pharmacogenetics 14:381–385
Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W (2005) Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C> affects mRNA stability. Pharmacogenet Genomics 15:693–704
Zamber CP, Lamba JK, Yasuda K, Farnum J, Thummel K, Schuetz JD, Schuetz EG (2003) Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. Pharmacogenetics 13:19–28
Kimchi-Sarfaty C, Gribar JJ, Gottesman MM (2002) Functional characterization of coding polymorphisms in the human MDR1 gene using a vaccinia virus expression system. Mol Pharmacol 62:1–6
Lin JH, Yamazaki M (2003) Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42:59–98
van de Steeg E, Wagenaar E, van der Kruijssen CM, Burggraaff JE, de Waart DR, Elferink RP, Kenworthy KE, Schinkel AH (2010) 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
van de Steeg E, van Esch A, Wagenaar E, van der Kruijssen CM, van Tellingen O, Kenworthy KE, Schinkel AH (2011) High impact of Oatp1a/1b transporters on in vivo disposition of the hydrophobic anticancer drug paclitaxel. Clin Cancer Res 17:294–301
Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CA, van der Valk MA, Robanus-Maandag EC, te Riele HP et al (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77:491–502
Sparreboom A, van Asperen J, Mayer U, Schinkel AH, Smit JW, Meijer DK, Borst P, Nooijen WJ, Beijnen JH, van Tellingen O (1997) Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A 94:2031–2035
Smit JW, Huisman MT, van Tellingen O, Wiltshire HR, Schinkel AH (1999) Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest 104:1441–1447
Saito T, Zhang ZJ, Ohtsubo T, Noda I, Shibamori Y, Yamamoto T, Saito H (2001) Homozygous disruption of the mdrla P-glycoprotein gene affects blood-nerve barrier function in mice administered with neurotoxic drugs. Acta Otolaryngol 121:735–742
Allen JD, Brinkhuis RF, van Deemter L, Wijnholds J, Schinkel AH (2000) Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance. Cancer Res 60:5761–5766
Allen JD, Brinkhuis RF, Wijnholds J, Schinkel AH (1999) The mouse Bcrp1/Mxr/Abcp gene: amplification and overexpression in cell lines selected for resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Res 59:4237–4241
Gallo JM, Li S, Guo P, Reed K, Ma J (2003) The effect of P-glycoprotein on paclitaxel brain and brain tumor distribution in mice. Cancer Res 63:5114–5117
Ejsing TB, Pedersen AD, Linnet K (2005) P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-drug interaction experiments. Hum Psychopharmacol 20:493–500
Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E, Chen C, Chen X, Choo E, Cianfrogna J, Cox LM, Gibbs JP, Gibbs MA, Hatch H, Hop CE, Kasman IN, Laperle J, Liu J, Liu X, Logman M, Maclin D, Nedza FM, Nelson F, Olson E, Rahematpura S, Raunig D, Rogers S, Schmidt K, Spracklin DK, Szewc M, Troutman M, Tseng E, Tu M, Van Deusen JW, Venkatakrishnan K, Walens G, Wang EQ, Wong D, Yasgar AS, Zhang C (2005) The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos 33:165–174
Ieiri I (2012) Functional significance of genetic polymorphisms in P-glycoprotein (MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2). Drug Metab Pharmacokinet 27:85–105
Johne A, Kopke K, Gerloff T, Mai I, Rietbrock S, Meisel C, Hoffmeyer S, Kerb R, Fromm MF, Brinkmann U, Eichelbaum M, Brockmoller J, Cascorbi I, Roots I (2002) Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 72:584–594
Verstuyft C, Schwab M, Schaeffeler E, Kerb R, Brinkmann U, Jaillon P, Funck-Brentano C, Becquemont L (2003) Digoxin pharmacokinetics and MDR1 genetic polymorphisms. Eur J Clin Pharmacol 58:809–812
Eichelbaum M, Fromm MF, Schwab M (2004) Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit 26:180–185
Sakaeda T (2005) MDR1 genotype-related pharmacokinetics: fact or fiction? Drug Metab Pharmacokinet 20:391–414
Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, Altman RB (2011) Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics 21:152–161
Lin SK, Su SF, Pan CH (2006) Higher plasma drug concentration in clozapine-treated schizophrenic patients with side effects of obsessive/compulsive symptoms. Ther Drug Monit 28:303–307
Sissung TM, Mross K, Steinberg SM, Behringer D, Figg WD, Sparreboom A, Mielke S (2006) Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur J Cancer 42:2893–2896
Schnepf R, Zolk O (2013) Effect of the ATP-binding cassette transporter ABCG2 on pharmacokinetics: experimental findings and clinical implications. Exp Opin Drug Metab Toxicol 9:287–306
Sparreboom A, Gelderblom H, Marsh S, Ahluwalia R, Obach R, Principe P, Twelves C, Verweij J, McLeod HL (2004) Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype. Clin Pharmacol Ther 76:38–44
Sparreboom A, Loos WJ, Burger H, Sissung TM, Verweij J, Figg WD, Nooter K, Gelderblom H (2005) Effect of ABCG2 genotype on the oral bioavailability of topotecan. Cancer Biol Ther 4:650–658
Mizuno T, Fukudo M, Terada T, Kamba T, Nakamura E, Ogawa O, Inui K, Katsura T (2012) Impact of genetic variation in breast cancer resistance protein (BCRP/ABCG2) on sunitinib pharmacokinetics. Drug Metab Pharmacokinet 27:631–639
Li J, Cusatis G, Brahmer J, Sparreboom A, Robey RW, Bates SE, Hidalgo M, Baker SD (2007) Association of variant ABCG2 and the pharmacokinetics of epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients. Cancer Biol Ther 6:432–438
Ieiri I, Suwannakul S, Maeda K, Uchimaru H, Hashimoto K, Kimura M, Fujino H, Hirano M, Kusuhara H, Irie S, Higuchi S, Sugiyama Y (2007) SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 82:541–547
Adkison KK, Vaidya SS, Lee DY, Koo SH, Li L, Mehta AA, Gross AS, Polli JW, Humphreys JE, Lou Y, Lee EJ (2010) Oral sulfasalazine as a clinical BCRP probe substrate: pharmacokinetic effects of genetic variation (C421A) and pantoprazole coadministration. J Pharm Sci 99:1046–1062
Ieiri I, Higuchi S, Sugiyama Y (2009) Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Exp Opin Drug Metab Toxicol 5:703–729
Giacomini KM, Balimane PV, Cho SK, Eadon M, Edeki T, Hillgren KM, Huang SM, Sugiyama Y, Weitz D, Wen Y, Xia CQ, Yee SW, Zimdahl H, Niemi M, International Transporter C (2013) International transporter consortium commentary on clinically important transporter polymorphisms. Clin Pharmacol Ther 94:23–26
Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M (2006) SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 16:873–879
Group SC, Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R (2008) SLCO1B1 variants and statin-induced myopathy – a genomewide study. N Eng J Med 359:789–799
Hillgren KM, Keppler D, Zur AA, Giacomini KM, Stieger B, Cass CE, Zhang L, International Transporter C (2013) Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther 94: 52–63
Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G, Prenen H, de Jong FA, Baker SD, Bates SE, Figg WD, Verweij J, Sparreboom A, Nooter K (2006) Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther 80:192–201
Chew SC, Singh O, Chen X, Ramasamy RD, Kulkarni T, Lee EJ, Tan EH, Lim WT, Chowbay B (2011) 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 67:1471–1478
Smith NF, Figg WD, Sparreboom A (2005) Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination. Exp Opin Drug Metab Toxicol 1:429–445
Zaher H, Meyer zu Schwabedissen HE, Tirona RG, Cox ML, Obert LA, Agrawal N, Palandra J, Stock JL, Kim RB, Ware JA (2008) Targeted disruption of murine organic aniontransporting polypeptide 1b2 (Oatp1b2/Slco1b2) significantly alters disposition of prototypical drug substrates pravastatin and rifampin. Mol Pharmacol 74:320–329
Romaine SP, Bailey KM, Hall AS, Balmforth AJ (2010) The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharmacogenomics J 10:1–11
Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R (2008) SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med 359:789–799
Wilke RA, Ramsey LB, Johnson SG, Maxwell WD, McLeod HL, Voora D, Krauss RM, Roden DM, Feng Q, Cooper-Dehoff RM, Gong L, Klein TE, Wadelius M, Niemi M (2012) The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther 92:112–117
U.S. Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. http://www.fda.gov/Drugs/Development ApprovalProcess/Development Resources/DrugInteractionsLabeling/ucm093664.htm. Accessed 10 Oct 2013
U.S. Food and Drug Administration. Guidance for industry: drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf. Accessed 11 Oct 2013
Minocha M et al (2012) Co-administration strategy to enhance brain accumulation of vandetanib by modulating P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) mediated efflux with m-TOR inhibitors. Int J Pharm 434(1–2):306–314
Zhou WJ et al (2012) Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein. Br J Pharmacol 166(5):1669–1683
Shi Z et al (2007) Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance. Cancer Res 67(22):11012–11020
Chuan Tang S et al (2013) Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer
Marchetti S et al (2008) Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice. Mol Cancer Ther 7(8):2280–2287
Marchetti S et al (2013) Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA. Invest New Drugs 31(5):1125–1135
Fox E, Bates SE (2007) Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther 7(4):447–459
van Zuylen L et al (2002) Disposition of docetaxel in the presence of P-glycoprotein inhibition by intravenous administration of R101933. Eur J Cancer 38(8):1090–1099
van Zuylen L et al (2000) The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel. Clin Cancer Res 6(4):1365–1371
Glaxo Group Ltd. Summary of product characteristics Tyverb (lapatinib). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000795/WC500044957.pdf. Accessed 22 Oct 2013
Morita N, Yasumori T, Nakayama K (2003) Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities. Biochem Pharmacol 65:1843–1852
Sakaeda T, Nakamura T, Horinouchi M et al (2001) MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res 18:1400–1404
Kameyama Y, Yamashita K, Kobayashi K, Hosokawa M, Chiba K (2005) Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet Genomics 15:513–522
Niemi M, Schaeffeler E, Lang T et al (2004) High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 14:429–440
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Sissung, T.M., Goey, A.K.L., Ley, A.M., Strope, J.D., Figg, W.D. (2014). Pharmacogenetics of Membrane Transporters: A Review of Current Approaches. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology, vol 1175. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0956-8_6
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