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Modeling Transport Processes and Their Implications for Chemical Disposition and Action

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Understanding the Dynamics of Biological Systems

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Abstract

In silico modeling has been used for a considerable period of time to aid in the understanding of drug action in the body. Such applications are vital to help understand the body’s response chemical exposure and hence predict drug action/ safety in vivo, as well as the extrapolation of such data from model animals to humans. However, until recently these models have not really included the role of active transport proteins in controlling drug disposition, which may influence the absorption, distribution and excretion of chemicals. This chapter will examine the development of in silico models for the increased understanding of drug transport processes, and how these can be used to aid in the prediction of an individual response to drug treatment.

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Notes

  1. 1.

    First-order kinetics is defined as any kinetic reaction where the rate of the reaction is not limited by the level of catalyzing protein, i.e., the protein is not saturated.

  2. 2.

    Mass action refers to the determination of reaction rate as the product of substrate concentration and the rate constant for the reaction (v = [S] ×k).

  3. 3.

    Zero-order kinetics is defined as any kinetic reaction where the rate of the reaction is limited by the level of catalyzing protein, i.e., where the reaction is saturated.

  4. 4.

    LogP is defined as the log10 of the [{ chemical in lipid (usually octanol)}] ∕ [{ chemical in water}] at a specified pH.

  5. 5.

    LogP is defined as the log10 of the [{ chemical in lipid (usually octanol)}] ∕ [{ chemical in water}] at pH 7.4.

  6. 6.

    http://www.celldesigner.org.

  7. 7.

    http://sbgn.org/Main_Page.

  8. 8.

    http://sbml.org/Main_Page.

  9. 9.

    http://www.copasi.org.

References

  1. P. Acharya, T. T. Tran, J. W. Polli, A. Ayrton, H. Ellens, and J. Bentz. P-glycoprotein (P-gp) expressed in a confluent monolayer of hMDR1-MDCKII cells has more than one efflux pathway with cooperative binding sites. Biochemistry, 45(51):15505–15519, 2006

    Article  PubMed  CAS  Google Scholar 

  2. S. Aouabdi, G. G. Gibson, and N. Plant. Transcriptional regulation of PXR: Identification of a PPRE within the proximal promoter responsible for fibrate-mediated transcriptional activation of PXR. Drug Metabolism and Disposition, 34(1):138–144, 2006

    Article  PubMed  CAS  Google Scholar 

  3. A. Ayrton and P. Morgan. Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica, 31(8–9):469–497, 2001

    Article  PubMed  CAS  Google Scholar 

  4. J. Bentz, T. T. Tran, J. W. Polli, A. Ayrton, and H. Ellens. The steady-state Michaelis-Menten analysis of P-glycoprotein mediated transport through a confluent cell monolayer cannot predict the correct Michaelis constant Km. Pharmaceutical Research, 22(10):1667–1677, 2005

    Article  PubMed  CAS  Google Scholar 

  5. J. G. M. Bessems and N. P. E. Vermeulen. Paracetamol (acetaminophen)-induced toxicity: Molecular and biochemical mechanism, analogues and protective approaches. Critical Reviews in Toxicology, 31(1):55–138, 2001

    Article  PubMed  CAS  Google Scholar 

  6. R. Buesen, M. Mock, A. Seidel, J. Jacob, and A. Lampen. Interaction between metabolism and transport of benzo[a]pyrene and its metabolites in enterocytes. Toxicology and Applied Pharmacology, 183(3):168–178, 2002

    Article  PubMed  CAS  Google Scholar 

  7. H. M. Coley. Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. Cancer Treatment Reviews, 34(4):378–390, 2008

    Article  PubMed  CAS  Google Scholar 

  8. A. Fick. Ueber diffusion. Annalen der Physik, 170:59–86, 1855

    Article  Google Scholar 

  9. A. Funahashi, N. Tanimura, M. Morohashi, and H. Kitano. CellDesigner: A process diagram editor for gene-regulatory and biochemical networks. Biosilico, 1:159–162, 2003

    Article  Google Scholar 

  10. G. G. Gibson and P. Skett. Introduction to drug metabolism. Nelson Thornes, Cheltenham, 3rd edition, 2001

    Google Scholar 

  11. H. Glavinas, D. Mehn, M. Jani, B. Oosterhuis, K. Heredi-Szabo, and P. Krajcsi. Utilization of membrane vesicle preparations to study drug-ABC transporter interactions. Expert Opinion in Drug Metabolism and Toxicology, 4(6):721–732, 2008

    Article  CAS  Google Scholar 

  12. S. Hoops, S. Sahle, R. Gauges, C. Lee, J. Pahle, N. Simus, M. Singhal, L. Xu, P. Mendes, and U. Kummer. COPASI – a COmplex PAthway SImulator. Bioinformatics, 22:3067–3074, 2006

    Article  PubMed  CAS  Google Scholar 

  13. E. Hopper-Borge, Z. S. Chen, I. Shchaveleva, M. G. Belinsky, and G. D. Kruh. Analysis of the drug resistance profile of multidrug resistance protein 7 (ABCC10): Resistance to docetaxel. Cancer Research, 64(14):4927–4930, 2004

    Article  PubMed  CAS  Google Scholar 

  14. K. Howe, G. G. Gibson, T. Coleman, and N. Plant. In silico and in vitro modelling of hepatocyte drug transport processes: Importance of ABCC2 expression levels in the disposition of carboxydichlorofluroscein. Drug Metabolism and Disposition, 37(2): 391–399, 2009

    Article  PubMed  CAS  Google Scholar 

  15. M. Hucka, A. Finney, H. M. Sauro, H. Bolouri, J. C. Doyle, H. Kitano, A. P. Arkin, B. J. Bornstein, D. Bray, A. Cornish-Bowden, A. A. Cuellar, S. Dronov, E. D. Gilles, M. Ginkel, V. Gor, I. I. Goryanin, W. J. Hedley, T. C. Hodgman, J. H. Hofmeyr, P. J. Hunter, N. S. Juty, J. L. Kasberger, A. Kremling, U. Kummer, N. Le Novere, L. M. Loew, D. Lucio, P. Mendes, E. Minch, E. D. Mjolsness, Y. Nakayama, M. R. Nelson, P. F. Nielsen, T. Sakurada, J. C. Schaff, B. E. Shapiro, T. S. Shimizu, H. D. Spence, J. Stelling, K. Takahashi, M. Tomita, J. Wagner, and J. Wang. The systems biology markup language (SBML): A medium for representation and exchange of biochemical network models. Bioinformatics, 19(4):524–531, 2003

    Article  PubMed  CAS  Google Scholar 

  16. S. H. Kim, F. R. Miller, L. Tait, J. Zheng, and R. F. Novak. Proteomic and phosphoproteomic alterations in benign, premalignant and tumor human breast epithelial cells and xenograft lesions: Biomarkers of progression. International Journal of Cancer, 124(12):2813–2828, 2009

    Article  CAS  Google Scholar 

  17. H. Kitano. Biological robustness. Nature Reviews Genetics, 5(11):826–837, 2004

    Article  PubMed  CAS  Google Scholar 

  18. H. Lennernas. Intestinal permeability and its relevance for absorption and elimination. Xenobiotica, 37(10–11):1015–1051, 2007

    Article  PubMed  CAS  Google Scholar 

  19. B. T. McGrogan, B. Gilmartin, D. N. Camey, and A. McCann. Taxanes, microtubules and chemoresistant breast cancer. Biochimica Et Biophysica Acta-Reviews on Cancer, 1785(2):96–132, 2008

    Article  CAS  Google Scholar 

  20. K. Palm, K. Luthman, J. Ros, J. Grasjo, and P. Artursson. Effect of molecular charge on intestinal epithelial drug transport: pH-dependent transport of cationic drugs. Journal of Pharmacology and Experimental Therapeutics, 291(2):435–443, 1999

    PubMed  CAS  Google Scholar 

  21. J.-M. Pascussi, S. Gerbal-Chaloin, J-M. Fabre, P. Maurel, and M-J. Vilarem. Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: Consequences on cytochrome P450 gene regulation. Molecular Pharmacology, 58(6):1441–1450, 2000a

    Google Scholar 

  22. J.-M. Pascussi, L. Drocourt, J.-M. Fabre, P. Maurel, and M.-J. Vilarem. Dexamethasone induces pregnane X receptor and retinoid X receptor-a expression in human hepatocytes: Synergistic increase of CYP3A4 induction by pregnane X receptor. Molecular Pharmacology, 58:361–372, 2000b

    PubMed  CAS  Google Scholar 

  23. N. Perriere, S. Yousif, S. Cazaubon, N. Chaverot, F. Bourasset, S. Cisternino, X. Decleves, S. Hori, T. Terasaki, M. Deli, J. M. Scherrmann, J. Temsamani, F. Roux, and P. O. Couraud. A functional in vitro model of rat blood-brain barrier for molecular analysis of efflux transporters. Brain Research, 1150:1–13, 2007

    Article  PubMed  CAS  Google Scholar 

  24. N. Plant. Molecular toxicology. Advanced Text. BIOS, London, 2003

    Google Scholar 

  25. N. Plant. Interaction networks: Coordinating responses to xenobiotic exposure. Toxicology, 202:21–32, 2004

    Article  PubMed  CAS  Google Scholar 

  26. N. Plant. The human cytochrome P450 3A sub-family: Transcriptional regulation, inter-individual variation and interaction networks. Biochimica Biophysica Acta, 1770 (3):478–488, 2007

    Article  CAS  Google Scholar 

  27. A. Poirier, T. Lave, R. Portmann, M. E. Brun, F. Senner, M. Kansy, H. P. Grimm, and C. Funk. Design, data analysis, and simulation of in vitro drug transport kinetic experiments using a mechanistic in vitro model. Drug Metabolism and Disposition, 36 (12):2434–2444, 2008

    Article  PubMed  CAS  Google Scholar 

  28. S. Ramaswamy, P. Tamayo, R. Rifkin, S. Mukherjee, C. H. Yeang, M. Angelo, C. Ladd, M. Reich, E. Latulippe, J. P. Mesirov, T. Poggio, W. Gerald, M. Loda, E. S. Lander, and T. R. Golub. Multiclass cancer diagnosis using tumor gene expression signatures. Proceedings of the National Academy of Sciences United States of America, 98(26): 15149–15154, 2001

    Article  CAS  Google Scholar 

  29. G. Rechkemmer. Transport of weak electrolytes. In M. Field and R. A. Frizzel, editors, Handbook of physiology, section 6: The gastrointestinal system, pp 371–388. American Physiological Society, Bethesda, 1991

    Google Scholar 

  30. R. A. Roberts, D. W. Nebert, J. A. Hickman, J. H. Richburg, and T. L. Goldsworthy. Perturbation of the mitosis/apoptosis balance: A fundamental mechanism in toxicology. Fundamental and Applied Toxicology, 38(2):107–115, 1997

    Article  PubMed  CAS  Google Scholar 

  31. A. Rostami-Hodjegan and G. T. Tucker. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nature Reviews Drug Discovery, 6(2):140–148, 2007

    Article  PubMed  CAS  Google Scholar 

  32. G. A. Sawada, C. L. Barsuhn, B. S. Lutzke, M. E. Houghton, G. E. Padbury, N. F. H. Ho, and T. J. Raub. Increased lipophilicity and subsequent cell partitioning decrease passive transcellular diffusion of novel, highly lipophilic antioxidants. Journal of Pharmacology and Experimental Therapeutics, 288(3):1317–1326, 1999

    PubMed  CAS  Google Scholar 

  33. G. Shinar, R. Milo, M. R. Martinez, and U. Alon. Input-output robustness in simple bacterial signaling systems. Proceedings of the National Academy of Sciences of the United States of America, 104(50):19931–19935, 2007

    Article  PubMed  CAS  Google Scholar 

  34. M. D. Slack, E. D. Martinez, L. F. Wu, and S. J. Altschuler. Characterizing heterogeneous cellular responses to perturbations. Proceedings of the National Academy of Sciences United States of America, 105(49):19306–19311, 2008

    Article  CAS  Google Scholar 

  35. D. Smirlis, R. Muangmoonchai, M. Edwards, I. R. Phillips, and E. A. Shephard. Orphan receptor promiscuity in the induction of cytochromes P450 by xenobiotics. Journal of Biological Chemistry, 276(16):12822–12826, 2001

    Article  PubMed  CAS  Google Scholar 

  36. C. Sotiriou and L. Pusztai. Gene-expression signatures in breast cancer. New England Journal of Medicine, 360(8):790–800, 2009

    Article  PubMed  CAS  Google Scholar 

  37. B. Tan, D. Piwnica-Worms, and L. Ratner. Multidrug resistance transporters and modulation. Current Opinion in Oncology, 12(5):450–458, 2000

    Article  PubMed  CAS  Google Scholar 

  38. T. N. Tozer and M. Rowland. Introduction to pharmacokinetics and pharmacodynamics: The quantitative basis of drug therapy. Lippincott Williams & Wilkins, Philadelphia, 2006

    Google Scholar 

  39. T. T. Tran, A. Mittal, T. Gales, B. Maleeff, T. Aldinger, J. W. Polli, A. Ayrton, H. Ellens, and J. Bentz. Exact kinetic analysis of passive transport across a polarized confluent MDCK cell monolayer modeled as a single barrier. Journal of Pharmaceutical Sciences, 93(8):2108–2123, 2004

    Article  PubMed  CAS  Google Scholar 

  40. T. T. Tran, A. Mittal, T. Aldinger, J. W. Polli, A. Ayrton, H. Ellens, and J. Bentz. The elementary mass action rate constants of P-gp transport for a confluent monolayer of MDCKII-hMDR1 cells. Biophysical Journal, 88(1):715–738, 2005

    Article  PubMed  CAS  Google Scholar 

  41. N. P. Ulrih, U. Adamlje, M. Nemec, and M. Sentjurc. Temperature- and pH-induced structural changes in the membrane of the hyperthermophilic archaeon Aeropyrum pernix K1. Journal of Membrane Biology, 219(1–3):1–8, 2007

    PubMed  CAS  Google Scholar 

  42. D. J. Villeneuve, S. L. Hembruff, Z. Veitch, M. Cecchetto, W. A. Dew, and A. M. Parissenti. cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Research and Treatment, 96(1):17–39, 2006

    Article  PubMed  CAS  Google Scholar 

  43. M. L. H. Vlaming, J. S. Lagas, and A. H. Schinkel. Physiological and pharmacological roles of ABCG2 (BCRP): Recent findings in Abcg2 knockout mice. Advanced Drug Delivery Reviews, 61(1):14–25, 2009

    Article  PubMed  CAS  Google Scholar 

  44. U. K. Walle and T. Walle. Taxol transport by human intestinal epithelial Caco-2 cells. Drug Metabolism and Disposition, 26(4):343–346, 1998

    PubMed  CAS  Google Scholar 

  45. R. E. Watkins, G. B. Wisely, L. B. Moore, J. L. Collins, M. H. Lambert, S. P. Williams, T. M. Willson, S. A. Kliewer, and M. R. Redinbo. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science, 292(5525): 2329–2333, 2001

    Article  PubMed  CAS  Google Scholar 

  46. P. Wils, A. Warnery, V. Phungba, S. Legrain, and D. Scherman. High liophilicity decreases drug transport across intestinal epithelial-cells. Journal of Pharmacology and Experimental Therapeutics, 269(2):654–658, 1994

    PubMed  CAS  Google Scholar 

  47. H. Xiao, P. Verdier-Pinard, N. Fernandez-Fuentes, B. Burd, R. Angeletti, A. Fiser, S. B. Horwitz, and G. A. Orr. Insights into the mechanism of microtubule stabilization by Taxol. Proceedings of the National Academy of Sciences of the United States of America, 103(27):10166–10173, 2006

    Article  PubMed  CAS  Google Scholar 

  48. K. A. Youdim, A. Avdeef, and N. J. Abbott. In vitro trans-monolayer permeability calculations: Often forgotten assumptions. Drug Discovery Today, 8(21):997–1003, 2003

    Article  PubMed  CAS  Google Scholar 

  49. Y. Zhou, E. Hopper-Borge, T. Shen, X. C. Huang, Z. Shi, Y. H. Kuang, T. Furukawa, S. Akiyama, X. X. Peng, C. R. Ashby, X. Chen, G. D. Kruh, and Z. S. Chen. Cepharanthine is a potent reversal agent for MRP7(ABCC10)-mediated multidrug resistance. Biochemical Pharmacology, 77(6):993–1001, 2009

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Centre for Toxicology, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK

    Nick Plant

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  1. Nano Systems Biology Research Group, Biomedical Sciences Research Institute, University of Ulster, Cromore Road, Coleraine, BT52 1SA, United Kingdom

    Werner Dubitzky

  2. Jack Birch Unit of Molecular Carcinogene, Department of Biology, University of York, York, United Kingdom

    Jennifer Southgate

  3. Biomedical Sciences Research Institute, Biomedical Sciences Research Institute, University of Ulster, Cromore Rd., Coleraine, BT52 1SA, United Kingdom

    Hendrik Fuß

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Plant, N. (2011). Modeling Transport Processes and Their Implications for Chemical Disposition and Action. In: Dubitzky, W., Southgate, J., Fuß, H. (eds) Understanding the Dynamics of Biological Systems. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7964-3_4

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