Skip to main content

Advertisement

SpringerLink
Log in

Pharmacogenetics of Membrane Transporters: An Update on Current Approaches

  • Review
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

This review provides an overview of the pharmacogenetics of membrane transporters including selected ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and OATPs (OATP1B1 and OATP1B3). Membrane transporters are heavily involved in drug clearance and alters drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have significant effects on the absorption, distribution, metabolism and excretion of compounds, and may alter pharmacodynamics of many agents. This review discusses the techniques used to identify substrates and inhibitors of these proteins and subsequently to assess the effect of genetic mutation on transport, both in vitro and in vivo. A comprehensive list of substrates for the major drug transporters is included. Finally, studies linking transporter genotype with clinical outcomes are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Borst, P., Evers, R., Kool, M., & Wijnholds, J. (2000). A family of drug transporters: The multidrug resistance-associated proteins. Journal of the National Cancer Institute, 92, 1295–1302.

    Article  CAS  Google Scholar 

  2. Dean, M., Rzhetsky, A., & Allikmets, R. (2001). The human ATP-binding cassette (ABC) transporter superfamily. Genome Research, 11, 1156–1166.

    Article  CAS  Google Scholar 

  3. Gottesman, M. M., & Ambudkar, S. V. (2001). Overview: ABC transporters and human disease. Journal of Bioenergetics and Biomembranes, 33, 453–458.

    Article  CAS  Google Scholar 

  4. Vasiliou, V., Vasiliou, K., & Nebert, D. W. (2009). Human ATP-binding cassette (ABC) transporter family. Human Genomics, 3, 281–290.

    CAS  Google Scholar 

  5. Lepper, E. R., Nooter, K., Verweij, J., Acharya, M. R., Figg, W. D., & Sparreboom, A. (2005). Mechanisms of resistance to anticancer drugs: The role of the polymorphic ABC transporters ABCB1 and ABCG2. Pharmacogenomics, 6, 115–138.

    Article  CAS  Google Scholar 

  6. Fojo, A. T., Shen, D. W., Mickley, L. A., Pastan, I., & Gottesman, M. M. (1987). Intrinsic drug resistance in human kidney cancer is associated with expression of a human multidrug-resistance gene. Journal of Clinical Oncology, 5, 1922–1927.

    CAS  Google Scholar 

  7. Maliepaard, M., Scheffer, G. L., Faneyte, I. F., van Gastelen, M. A., Pijnenborg, A. C., Schinkel, A. H., et al. (2001). Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Research, 61, 3458–3464.

    CAS  Google Scholar 

  8. Schellens, J. H., Malingre, M. M., Kruijtzer, C. M., Bardelmeijer, H. A., van Tellingen, O., Schinkel, A. H., et al. (2000). Modulation of oral bioavailability of anticancer drugs: from mouse to man. European Journal of Pharmaceutical Science, 12, 103–110.

    Article  CAS  Google Scholar 

  9. Schinkel, A. H., Mayer, U., Wagenaar, E., Mol, C. A., van Deemter, L., Smit, J. J., et al. (1997). Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proceedings of the National Academy of Sciences USA, 94, 4028–4033.

    Article  CAS  Google Scholar 

  10. Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M. M., Pastan, I., & Willingham, M. C. (1987). Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proceedings of the National Academy of Sciences USA, 84, 7735–7738.

    Article  CAS  Google Scholar 

  11. Xiao, J. J., Foraker, A. B., Swaan, P. W., Liu, S., Huang, Y., Dai, Z., et al. (2005). Efflux of depsipeptide FK228 (FR901228, NSC-630176) is mediated by P-glycoprotein and multidrug resistance-associated protein 1. Journal of Pharmacology and Experimental Therapeutics, 313, 268–276.

    Article  CAS  Google Scholar 

  12. Chaudhary, P. M., & Roninson, I. B. (1991). Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell, 66, 85–94.

    Article  CAS  Google Scholar 

  13. Eichelbaum, M., Fromm, M. F., & Schwab, M. (2004). Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Therapeutic Drug Monitoring, 26, 180–185.

    Article  CAS  Google Scholar 

  14. Fromm, M. F. (2004). Importance of P-glycoprotein at blood-tissue barriers. Trends in Pharmacological Sciences, 25, 423–429.

    Article  CAS  Google Scholar 

  15. Meissner, K., Sperker, B., Karsten, C., Zu Schwabedissen, H. M., Seeland, U., Bohm, M., et al. (2002). Expression and localization of P-glycoprotein in human heart: Effects of cardiomyopathy. Journal of Histochemistry and Cytochemistry, 50, 1351–1356.

    CAS  Google Scholar 

  16. Rao, V. V., Dahlheimer, J. L., Bardgett, M. E., Snyder, A. Z., Finch, R. A., Sartorelli, A. C., et al. (1999). Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proceedings of the National Academy of Sciences USA, 96, 3900–3905.

    Article  CAS  Google Scholar 

  17. Saito, T., Zhang, Z. J., Ohtsubo, T., Noda, I., Shibamori, Y., Yamamoto, T., et al. (2001). Homozygous disruption of the mdrla P-glycoprotein gene affects blood-nerve barrier function in mice administered with neurotoxic drugs. Acta Oto-Laryngologica, 121, 735–742.

    Article  CAS  Google Scholar 

  18. Wijnholds, J., deLange, E. C., Scheffer, G. L., van den Berg, D. J., Mol, C. A., van der Valk, M., et al. (2000). Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. Journal of Clinical Investigation, 105, 279–285.

    Article  CAS  Google Scholar 

  19. Borst, P., Evers, R., Kool, M., & Wijnholds, J. (1999). The multidrug resistance protein family. Biochimica et Biophysica Acta, 1461, 347–357.

    Article  CAS  Google Scholar 

  20. Cascorbi, I. (2006). Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacology and Therapeutics, 112, 457–473.

    Article  CAS  Google Scholar 

  21. Deeley, R. G., & Cole, S. P. (2006). Substrate recognition and transport by multidrug resistance protein 1 (ABCC1). FEBS Letters, 580, 1103–1111.

    Article  CAS  Google Scholar 

  22. Ho, R. H., & Kim, R. B. (2005). Transporters and drug therapy: Implications for drug disposition and disease. Clinical Pharmacology and Therapeutics, 78, 260–277.

    Article  CAS  Google Scholar 

  23. Smith, N. F., Figg, W. D., & Sparreboom, A. (2005). Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination. Expert Opinion on Drug Metabolism and Toxicology, 1, 429–445.

    Article  CAS  Google Scholar 

  24. Hamada, A., Sissung, T., Price, D. K., Danesi, R., Chau, C. H., Sharifi, N., et al. (2008). Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer. Clinical Cancer Research, 14, 3312–3318.

    Article  CAS  Google Scholar 

  25. Lee, W., Belkhiri, A., Lockhart, A. C., Merchant, N., Glaeser, H., Harris, E. I., et al. (2008). Overexpression of OATP1B3 confers apoptotic resistance in colon cancer. Cancer Research, 68, 10315–10323.

    Article  CAS  Google Scholar 

  26. Narita, M., Hatano, E., Arizono, S., Miyagawa-Hayashino, A., Isoda, H., Kitamura, K., et al. (2009). Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. Journal of Gastroenterology, 44, 793–798.

    Article  CAS  Google Scholar 

  27. Sharom, F. J. (2008). ABC multidrug transporters: Structure, function and role in chemoresistance. Pharmacogenomics, 9, 105–127.

    Article  CAS  Google Scholar 

  28. Kurata, Y., Ieiri, I., Kimura, M., Morita, T., Irie, S., Urae, A., et al. (2002). Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clinical Pharmacology and Therapeutics, 72, 209–219.

    Article  CAS  Google Scholar 

  29. Tanabe, M., Ieiri, I., Nagata, N., Inoue, K., Ito, S., Kanamori, Y., et al. (2001). Expression of P-glycoprotein in human placenta: Relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. Journal of Pharmacology and Experimental Therapeutics, 297, 1137–1143.

    CAS  Google Scholar 

  30. Yi, S. Y., Hong, K. S., Lim, H. S., Chung, J. Y., Oh, D. S., Kim, J. R., et al. (2004). A variant 2677A allele of the MDR1 gene affects fexofenadine disposition. Clinical Pharmacology and Therapeutics, 76, 418–427.

    Article  CAS  Google Scholar 

  31. Sun, J., He, Z. G., Cheng, G., Wang, S. J., Hao, X. H., & Zou, M. J. (2004). Multidrug resistance P-glycoprotein: Crucial significance in drug disposition and interaction. Medical Science Monitor, 10, RA5–RA14.

    CAS  Google Scholar 

  32. Kimchi-Sarfaty, C., Oh, J. M., Kim, I. W., Sauna, Z. E., Calcagno, A. M., Ambudkar, S. V., et al. (2007). A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science, 315, 525–528.

    Article  CAS  Google Scholar 

  33. Tsai, C. J., Sauna, Z. E., Kimchi-Sarfaty, C., Ambudkar, S. V., Gottesman, M. M., & Nussinov, R. (2008). Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima. Journal of Molecular Biology, 383, 281–291.

    Article  CAS  Google Scholar 

  34. Tamura, A., Wakabayashi, K., Onishi, Y., Takeda, M., Ikegami, Y., Sawada, S., et al. (2007). Re-evaluation and functional classification of non-synonymous single nucleotide polymorphisms of the human ATP-binding cassette transporter ABCG2. Cancer Science, 98, 231–239.

    Article  CAS  Google Scholar 

  35. Mizuarai, S., Aozasa, N., & Kotani, H. (2004). Single nucleotide polymorphisms result in impaired membrane localization and reduced atpase activity in multidrug transporter ABCG2. International Journal of Cancer, 109, 238–246.

    Article  CAS  Google Scholar 

  36. de Jong, F. A., Marsh, S., Mathijssen, R. H., King, C., Verweij, J., Sparreboom, A., et al. (2004). ABCG2 pharmacogenetics: Ethnic differences in allele frequency and assessment of influence on irinotecan disposition. Clinical Cancer Research, 10, 5889–5894.

    Article  Google Scholar 

  37. Imai, Y., Nakane, M., Kage, K., Tsukahara, S., Ishikawa, E., Tsuruo, T., et al. (2002). C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. Molecular Cancer Therapeutics, 1, 611–616.

    CAS  Google Scholar 

  38. Kondo, C., Suzuki, H., Itoda, M., Ozawa, S., Sawada, J., Kobayashi, D., et al. (2004). Functional analysis of SNPs variants of BCRP/ABCG2. Pharmaceutical Research, 21, 1895–1903.

    Article  CAS  Google Scholar 

  39. Allen, J. D., Jackson, S. C., & Schinkel, A. H. (2002). A mutation hot spot in the Bcrp1 (Abcg2) multidrug transporter in mouse cell lines selected for Doxorubicin resistance. Cancer Research, 62, 2294–2299.

    CAS  Google Scholar 

  40. Honjo, Y., Hrycyna, C. A., Yan, Q. W., Medina-Perez, W. Y., Robey, R. W., van de Laar, A., et al. (2001). Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells. Cancer Research, 61, 6635–6639.

    CAS  Google Scholar 

  41. Robey, R. W., Honjo, Y., Morisaki, K., Nadjem, T. A., Runge, S., Risbood, M., et al. (2003). Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity. British Journal of Cancer, 89, 1971–1978.

    Article  CAS  Google Scholar 

  42. Robey, R. W., Steadman, K., Polgar, O., Morisaki, K., Blayney, M., Mistry, P., et al. (2004). Pheophorbide a is a specific probe for ABCG2 function and inhibition. Cancer Research, 64, 1242–1246.

    Article  CAS  Google Scholar 

  43. Letourneau, I. J., Deeley, R. G., & Cole, S. P. (2005). Functional characterization of non-synonymous single nucleotide polymorphisms in the gene encoding human multidrug resistance protein 1 (MRP1/ABCC1). Pharmacogenetics Genomics, 15, 647–657.

    Article  CAS  Google Scholar 

  44. Oselin, K., Mrozikiewicz, P. M., 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. European Journal of Clinical Pharmacology, 59, 347–350.

    Article  CAS  Google Scholar 

  45. Tirona, R. G., Leake, B. F., Merino, G., & Kim, R. B. (2001). Polymorphisms in OATP-C: Identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. Journal of Biological Chemistry, 276, 35669–35675.

    Article  CAS  Google Scholar 

  46. Nozawa, T., Nakajima, M., Tamai, I., Noda, K., Nezu, J., Sai, Y., et al. (2002). Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): Allele frequencies in the Japanese population and functional analysis. Journal of Pharmacology and Experimental Therapeutics, 302, 804–813.

    Article  CAS  Google Scholar 

  47. Ho, R. H., Choi, L., Lee, W., Mayo, G., Schwarz, U. I., Tirona, R. G., et al. (2007). Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenetics Genomics, 17, 647–656.

    Article  CAS  Google Scholar 

  48. Mwinyi, J., Kopke, K., Schaefer, M., Roots, I., & Gerloff, T. (2008). Comparison of SLCO1B1 sequence variability among German, Turkish, and African populations. European Journal of Clinical Pharmacology, 64, 257–266.

    Article  CAS  Google Scholar 

  49. Smith, N. F., Marsh, S., Scott-Horton, T. J., Hamada, A., Mielke, S., Mross, K., et al. (2007). Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics. Clinical Pharmacology and Therapeutics, 81, 76–82.

    Article  CAS  Google Scholar 

  50. Colburn, W. A. (2003). Biomarkers in drug discovery and development: From target identification through drug marketing. Journal of Clinical Pharmacology, 43, 329–341.

    Article  Google Scholar 

  51. Deeken, J. (2009). The Affymetrix DMET platform and pharmacogenetics in drug development. Current Opinion in Molecular Therapy, 11, 260–268.

    CAS  Google Scholar 

  52. Cole, S. P., Bhardwaj, G., Gerlach, J. H., Mackie, J. E., Grant, C. E., Almquist, K. C., et al. (1992). Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science, 258, 1650–1654.

    Article  CAS  Google Scholar 

  53. Hesselink, D. A., van Schaik, R. H., van der Heiden, I. P., van der Werf, M., Gregoor, P. J., Lindemans, J., et al. (2003). Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clinical Pharmacology and Therapeutics, 74, 245–254.

    Article  CAS  Google Scholar 

  54. Noe, B., Hagenbuch, B., Stieger, B., & Meier, P. J. (1997). Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proceedings of the National Academy of Sciences USA, 94, 10346–10350.

    Article  CAS  Google Scholar 

  55. Wang, X., Wolkoff, A. W., & Morris, M. E. (2005). Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1 (OATP-C) modulators. Drug Metabolism and Disposition, 33, 1666–1672.

    Article  CAS  Google Scholar 

  56. Cvetkovic, M., Leake, B., Fromm, M. F., Wilkinson, G. R., & Kim, R. B. (1999). OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metabolism and Disposition, 27, 866–871.

    CAS  Google Scholar 

  57. Aszalos, A. (2004). P-glycoprotein-based drug–drug interactions: Preclinical methods and relevance to clinical observations. Archives of Pharmacal Research, 27, 127–135.

    Article  CAS  Google Scholar 

  58. Smith, N. F., Acharya, M. R., Desai, N., Figg, W. D., & Sparreboom, A. (2005). Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Cancer Biology & Therapy, 4, 815–818.

    Article  CAS  Google Scholar 

  59. Boumendjel, A., McLeer-Florin, A., Champelovier, P., Allegro, D., Muhammad, D., Souard, F., et al. (2009). A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in vitro and in vivo glioblastoma models. BMC Cancer, 9, 242.

    Article  Google Scholar 

  60. Hitzl, M., Drescher, S., van der Kuip, H., Schaffeler, E., Fischer, J., Schwab, M., et al. (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.

    Article  CAS  Google Scholar 

  61. Schaefer, M., Roots, I., & Gerloff, T. (2005). In vitro transport characteristics discriminate wildtype mdr1 (abcb1) from ala893ser and ala893thr polymorphisms. European Journal of Clinical Pharmacology, 61, 718.

    Google Scholar 

  62. Ishikawa, T., Sakurai, A., Kanamori, Y., Nagakura, M., Hirano, H., Takarada, Y., et al. (2005). High-speed screening of human ATP-binding cassette transporter function and genetic polymorphisms: New strategies in pharmacogenomics. Methods in Enzymology, 400, 485–510.

    Article  CAS  Google Scholar 

  63. Morisaki, K., Robey, R. W., Ozvegy-Laczka, C., Honjo, Y., Polgar, O., Steadman, K., et al. (2005). Single nucleotide polymorphisms modify the transporter activity of ABCG2. Cancer Chemotherapy and Pharmacology, 56, 161–172.

    Article  CAS  Google Scholar 

  64. Zhang, Y., Gupta, A., Wang, H., Zhou, L., Vethanayagam, R. R., Unadkat, J. D., et al. (2005). BCRP transports dipyridamole and is inhibited by calcium channel blockers. Pharmaceutical Research, 22, 2023–2034.

    Article  CAS  Google Scholar 

  65. Nakamura, Y., Oka, M., Soda, H., Shiozawa, K., Yoshikawa, M., Itoh, A., et al. (2005). Gefitinib (“Iressa”, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. Cancer Research, 65, 1541–1546.

    Article  CAS  Google Scholar 

  66. 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.

    Article  CAS  Google Scholar 

  67. Michalski, C., Cui, Y., Nies, A. T., Nuessler, A. K., Neuhaus, P., Zanger, U. M., et al. (2002). A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. Journal of Biological Chemistry, 277, 43058–43063.

    Article  CAS  Google Scholar 

  68. 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 Metabolism and Disposition, 33, 434–439.

    Article  CAS  Google Scholar 

  69. Tirona, R. G., Leake, B. F., Wolkoff, A. W., & Kim, R. B. (2003). Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. Journal of Pharmacology and Experimental Therapeutics, 304, 223–228.

    Article  CAS  Google Scholar 

  70. Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H. P., Brockmoller, J., Johne, A., et al. (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. Proceedings of the National Academy of Sciences USA, 97, 3473–3478.

    Article  CAS  Google Scholar 

  71. Song, P., Lamba, J. K., Zhang, L., Schuetz, E., Shukla, N., Meibohm, B., et al. (2006). G2677T and C3435T genotype and haplotype are associated with hepatic ABCB1 (MDR1) expression. Journal of Clinical Pharmacology, 46, 373–379.

    Article  CAS  Google Scholar 

  72. Meissner, K., Jedlitschky, G., Meyer zu Schwabedissen, H., Dazert, P., Eckel, L., Vogelgesang, S., et al. (2004). Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms. Pharmacogenetics, 14, 381–385.

    Article  CAS  Google Scholar 

  73. Wang, D., Johnson, A. D., Papp, A. C., Kroetz, D. L., & Sadee, W. (2005). Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenetics Genomics, 15, 693–704.

    Article  CAS  Google Scholar 

  74. Zamber, C. P., Lamba, J. K., Yasuda, K., Farnum, J., Thummel, K., Schuetz, J. D., et al. (2003). Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. Pharmacogenetics, 13, 19–28.

    Article  CAS  Google Scholar 

  75. 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.

    Article  CAS  Google Scholar 

  76. Kimchi-Sarfaty, C., Gribar, J. J., & Gottesman, M. M. (2002). Functional characterization of coding polymorphisms in the human MDR1 gene using a vaccinia virus expression system. Molecular Pharmacology, 62, 1–6.

    Article  CAS  Google Scholar 

  77. Lin, J. H., & Yamazaki, M. (2003). Role of P-glycoprotein in pharmacokinetics: Clinical implications. Clinical Pharmacokinetics, 42, 59–98.

    Article  CAS  Google Scholar 

  78. Schinkel, A. H., Smit, J. J., van Tellingen, O., Beijnen, J. H., Wagenaar, E., van Deemter, L., 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.

    Article  CAS  Google Scholar 

  79. Sparreboom, A., van Asperen, J., Mayer, U., Schinkel, A. H., Smit, J. W., Meijer, D. K., et al. (1997). Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proceedings of the National Academy of Sciences USA, 94, 2031–2035.

    Article  CAS  Google Scholar 

  80. Smit, J. W., Huisman, M. T., van Tellingen, O., Wiltshire, H. R., & Schinkel, A. H. (1999). Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. Journal of Clinical Investigation, 104, 1441–1447.

    Article  CAS  Google Scholar 

  81. Allen, J. D., Brinkhuis, R. F., van Deemter, L., Wijnholds, J., & Schinkel, A. H. (2000). Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance. Cancer Research, 60, 5761–5766.

    CAS  Google Scholar 

  82. Allen, J. D., Brinkhuis, R. F., Wijnholds, J., & Schinkel, A. H. (1999). The mouse Bcrp1/Mxr/Abcp gene: Amplification and overexpression in cell lines selected for resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Research, 59, 4237–4241.

    CAS  Google Scholar 

  83. Zhou, L., Schmidt, K., Nelson, F. R., Zelesky, V., Troutman, M. D., & Feng, B. (2009). The effect of breast cancer resistance protein and P-glycoprotein on the brain penetration of flavopiridol, imatinib mesylate (Gleevec), prazosin, and 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid (PF-407288) in mice. Drug Metabolism and Disposition, 37, 946–955.

    Article  CAS  Google Scholar 

  84. Gallo, J. M., Li, S., Guo, P., Reed, K., & Ma, J. (2003). The effect of P-glycoprotein on paclitaxel brain and brain tumor distribution in mice. Cancer Research, 63, 5114–5117.

    CAS  Google Scholar 

  85. Ejsing, T. B., Pedersen, A. D., & 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. Human Psychopharmacology, 20, 493–500.

    Article  CAS  Google Scholar 

  86. Doran, A., Obach, R. S., Smith, B. J., Hosea, N. A., Becker, S., Callegari, E., et al. (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 Metabolism and Disposition, 33, 165–174.

    Article  CAS  Google Scholar 

  87. Johne, A., Kopke, K., Gerloff, T., Mai, I., Rietbrock, S., Meisel, C., et al. (2002). Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clinical Pharmacology and Therapeutics, 72, 584–594.

    Article  CAS  Google Scholar 

  88. Verstuyft, C., Schwab, M., Schaeffeler, E., Kerb, R., Brinkmann, U., Jaillon, P., et al. (2003). Digoxin pharmacokinetics and MDR1 genetic polymorphisms. European Journal of Clinical Pharmacology, 58, 809–812.

    CAS  Google Scholar 

  89. Sakaeda, T. (2005). MDR1 genotype-related pharmacokinetics: Fact or fiction? Drug Metabolism and Pharmacokinetics, 20, 391–414.

    Article  CAS  Google Scholar 

  90. Lin, S. K., Su, S. F., & Pan, C. H. (2006). Higher plasma drug concentration in clozapine-treated schizophrenic patients with side effects of obsessive/compulsive symptoms. Therapeutic Drug Monitoring, 28, 303–307.

    Article  CAS  Google Scholar 

  91. Sissung, T. M., Mross, K., Steinberg, S. M., Behringer, D., Figg, W. D., Sparreboom, A., et al. (2006). Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. European Journal of Cancer, 42, 2893–2896.

    Article  CAS  Google Scholar 

  92. Keskitalo, J. E., Zolk, O., Fromm, M. F., Kurkinen, K. J., Neuvonen, P. J., & Niemi, M. (2009). ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clinical Pharmacology and Therapeutics, 86, 197–203.

    Article  CAS  Google Scholar 

  93. van Erp, N. P., Eechoute, K., van der Veldt, A. A., Haanen, J. B., Reyners, A. K., Mathijssen, R. H., et al. (2009). Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. Journal of Clinical Oncology, 27, 4406–4412.

    Article  CAS  Google Scholar 

  94. Niemi, M., Schaeffeler, E., Lang, T., Fromm, M. F., Neuvonen, M., Kyrklund, C., 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.

    Article  CAS  Google Scholar 

  95. Niemi, M., Neuvonen, P. J., Hofmann, U., Backman, J. T., Schwab, M., Lutjohann, D., et al. (2005). Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17. Pharmacogenetics Genomics, 15, 303–309.

    Article  CAS  Google Scholar 

  96. Tachibana-Iimori, R., Tabara, Y., Kusuhara, H., Kohara, K., Kawamoto, R., Nakura, J., et al. (2004). Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors. Drug Metabolism and Pharmacokinetics, 19, 375–380.

    Article  CAS  Google Scholar 

  97. Sharifi, N., Hamada, A., Sissung, T., Danesi, R., Venzon, D., Baum, C., et al. (2008). A polymorphism in a transporter of testosterone is a determinant of androgen independence in prostate cancer. BJU International, 102, 617–621.

    Article  CAS  Google Scholar 

  98. Schaefer, M., Roots, I., & Gerloff, T. (2006). In vitro transport characteristics discriminate wild-type ABCB1 (MDR1) from ALA893SER and ALA893THR polymorphisms. Pharmacogenetics Genomics, 16, 855–861.

    Article  CAS  Google Scholar 

  99. Kim, R. B., Leake, B. F., Choo, E. F., Dresser, G. K., Kubba, S. V., Schwarz, U. I., et al. (2001). Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clinical Pharmacology and Therapeutics, 70, 189–199.

    Article  CAS  Google Scholar 

  100. Goh, B. C., Lee, S. C., Wang, L. Z., Fan, L., Guo, J. Y., Lamba, J., et al. (2002). Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. Journal of Clinical Oncology, 20, 3683–3690.

    Article  CAS  Google Scholar 

  101. Isla, D., Sarries, C., Rosell, R., Alonso, G., Domine, M., Taron, M., et al. (2004). Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Annals of Oncology, 15, 1194–1203.

    Article  CAS  Google Scholar 

  102. Puisset, F., Chatelut, E., Dalenc, F., Busi, F., Cresteil, T., Azema, J., et al. (2004). Dexamethasone as a probe for docetaxel clearance. Cancer Chemotherapy and Pharmacology, 54, 265–272.

    Article  CAS  Google Scholar 

  103. Wils, P., Phung-Ba, V., Warnery, A., Lechardeur, D., Raeissi, S., Hidalgo, I. J., et al. (1994). Polarized transport of docetaxel and vinblastine mediated by P-glycoprotein in human intestinal epithelial cell monolayers. Biochemical Pharmacology, 48, 1528–1530.

    Article  CAS  Google Scholar 

  104. Sparreboom, A., Loos, W. J., Burger, H., Sissung, T. M., Verweij, J., Figg, W. D., et al. (2005). Effect of ABCG2 genotype on the oral bioavailability of topotecan. Cancer Biology & Therapy, 4, 650–658.

    Article  CAS  Google Scholar 

  105. Gardner, E. R., Burger, H., van Schaik, R. H., van Oosterom, A. T., de Bruijn, E. A., Guetens, G., et al. (2006). Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clinical Pharmacology and Therapeutics, 80, 192–201.

    Article  CAS  Google Scholar 

  106. Mwinyi, J., Johne, A., Bauer, S., Roots, I., & Gerloff, T. (2004). Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clinical Pharmacology and Therapeutics, 75, 415–421.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 and HHSN261200800001E.* The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government (*ERG). This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Author information

Authors and Affiliations

  1. Clinical Pharmacology Program, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD, 20892, USA

    Tristan M. Sissung & William D. Figg

  2. Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD, 20892, USA

    Caitlin E. Baum, C. Tyler Kirkland, Rui Gao & William D. Figg

  3. Clinical Pharmacology Program, SAIC-Frederick, NCI-Frederick, Frederick, MD, 21702, USA

    Erin R. Gardner

Authors
  1. Tristan M. Sissung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caitlin E. Baum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Tyler Kirkland
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erin R. Gardner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William D. Figg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William D. Figg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sissung, T.M., Baum, C.E., Kirkland, C.T. et al. Pharmacogenetics of Membrane Transporters: An Update on Current Approaches. Mol Biotechnol 44, 152–167 (2010). https://doi.org/10.1007/s12033-009-9220-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12033-009-9220-6

Keywords

Search

Navigation