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The applicability of computational chemistry in the evaluation and prediction of drug transport properties

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Perspectives in Drug Discovery and Design

Abstract

We have investigated the relationship between drug retention in immobilized liposome partitioning chromatography and liposome partitioning and found a strong linear correlation. Separate linear relationships were found depending on the charge of the compound when liposome chromatographic measurements were related to the octanol/water partition coefficients. We have also investigated the importance of the water/octanol partition coefficient in quantitative structure–property relationships related to drug transport properties. The studies show that the inclusion of a parameter related to lipophilicity causes only, at best, a marginal increase in internal predictivity and, at worst, a decrease in external predictivity. The studies also show that parameters related to hydrogen bonding, polarizability and size are important properties that need to be included in quantitative models for drug transport processes. We believe that the use of multivariate characterizations of compounds based on non-composite parameters may result in better and more predictive models compared with models based on parameters of a more composite nature when investigating the possibilities to establish quantitative structure–property relationships.

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References

  1. Mouritsen, O.G. and Jorgensen, K., Pharm. Res., 15 (1998) 1507.

    Article  PubMed  CAS  Google Scholar 

  2. Seydel, J.K., Albores Velasco, M., Coats, E.A., Cordes, H.P., Kunz, B. and Wiese, W., Quant. Struct.-Act. Relat., 11 (1992) 205.

    CAS  Google Scholar 

  3. Herbette, L.G., Rhodes, D.G. and Preston Mason, R., Drug Des. Deliv., 7 (1991) 75.

    PubMed  CAS  Google Scholar 

  4. Hansch, C., Maloney, P.P., Fujita, T. and Muir, R.M., Nature, 194 (1962) 178.

    Article  CAS  Google Scholar 

  5. Tute, M.S., In Pliska, V., Testa, B. and van de Waterbeemd, H. (Eds.) Lipophilicity in Drug Action and Toxicology, Vol. 4, VCH, Weinheim, 1996, pp. 7–26.

    Google Scholar 

  6. Lundahl, P. and Beigi, F., Adv. Drug Deliv. Rev., 23 (1997) 221.

    Article  CAS  Google Scholar 

  7. Beigi, F., Yang, Q. and Lundahl, P., J. Chromatogr. A, 704 (1995) 315.

    Article  CAS  Google Scholar 

  8. Pidgeon, C., Ong, S., Liu, H., Qiu, X., Pidgeon, M., Dantzig, A.H., Munroe, J., Hornback, W.J., Kasher, J.S., Glunz, L. and Szczerba, T., J. Med. Chem., 38 (1995) 590.

    Article  PubMed  CAS  Google Scholar 

  9. Beigi, F., Gootschalk, I., Lagerquist Hägglund, C., Haneskog, L., Brekkan, E., Zhang, Y., Österberg, T. and Lundahl, P., Int. J. Pharm., 164 (1998) 129.

    Article  CAS  Google Scholar 

  10. Avdeef, A., Box, K.J., Comer, J.E., Hibbert, C. and Tam, K.Y., Pharm. Res., 15 (1998) 209.

    Article  PubMed  CAS  Google Scholar 

  11. Austin, R.P., Davis, A.M. and Manners, C.N., J. Pharm. Sci., 84 (1995) 1180.

    PubMed  CAS  Google Scholar 

  12. Irvine, J.D., Takahashi, L., Lockhart, K., Cheong, J., Tolan, J.W., Selick, H.E. and Grove, R., J. Pharm. Sci., 88 (1999) 28.

    Article  PubMed  CAS  Google Scholar 

  13. Artursson, P. and Karlsson, J., Biochem. Biophys. Res. Commun., 175 (1991) 880.

    Article  PubMed  CAS  Google Scholar 

  14. Camenisch, G., Alsenz, J., van de Waterbeemd, H. and Folkers, G., Eur. J. Pharm. Sci., 6 (1998) 313.

    Article  CAS  Google Scholar 

  15. Norinder, U., Österberg, T. and Artursson, P., Pharm. Res., 14 (1997) 1786.

    Article  PubMed  CAS  Google Scholar 

  16. Norinder, U., Sjöberg, P. and Österberg, T., J. Pharm. Sci., 87 (1998) 952.

    Article  PubMed  CAS  Google Scholar 

  17. Norinder, U., Österberg, T. and Artursson, P., Eur. J. Pharm. Sci., 8 (1999) 49.

    Article  PubMed  CAS  Google Scholar 

  18. MacroModel version 5.5, Department of Chemistry, Columbia University, New York, NY.

  19. Spartan version 4.1, Wavefunction, Inc., Irvine, CA.

  20. MolSurf version 2.0, Qemist AB, Karlskoga, Sweden.

  21. Sjöberg, P., In van de Waterbeemd, H., Testa, B. and Folkers, G. (Eds.) Computer-Assisted Lead Finding and Optimization: Current Tools for Medicinal Chemistry, VHCA, Basel, 1997, pp. 83–92.

    Google Scholar 

  22. Sybyl version 6.5.1A, Tripos, Inc., St. Louis, MO.

  23. ACD/logD Batch version 3.50, Advanced Chemistry Development, Inc., Toronto, ON.

  24. ACD/logP Batch version 3.50, Advanced Chemistry Development, Inc., Toronto, ON.

  25. Marengo, E. and Todeschini, R., Chem. Intell. Lab. Systems, 16 (1992) 37.

    Article  CAS  Google Scholar 

  26. Jackson, J.E., A Users Guide to Principal Components, Wiley & Sons, New York, NY, 1991.

    Book  Google Scholar 

  27. Joliffe, I.T., Principal Component Analysis, Springer Verlag, New York, NY, 1986.

    Google Scholar 

  28. Wold, S., Johansson, E. and Cocchi, M., In Kubinyi, H. (Ed.) 3D QSAR in Drug Design, ESCOM, Leiden, 1993, pp. 523–550.

    Google Scholar 

  29. Wold, S., Technometrics, 20 (1979) 379.

    Google Scholar 

  30. Wold, S., Albano, C., Dunn III, W.J., Edlund, U., Esbensen, K., Geladi, P., Johansson, E., Lindberg, W. and Sjöström, M., In Kowalski, B.R. (Ed.) Chemometrics-Mathematics and Statistics in Chemistry, Reidel, Dordrecht, 1984, pp. 17–95.

    Google Scholar 

  31. Craig, P.N., Cumulative Subject Index and Drug Compendium, Vol. 6, In Hansch, C., Sammes, P.G. and Taylor, J.B. (Eds.) Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, 1990, pp. 237–991.

    Google Scholar 

  32. Palm, K., Luthman, K., Ungell, A.L., Strandlund, G. and Artursson, P., J. Pharm. Sci., 85 (1996) 32.

    Google Scholar 

  33. Barbato, F., Caliendo, G., la Rotonda, M.I., Morrica, P., Silipo, C. and Vittoria, A., Farmaco, 45 (1990) 647.

    PubMed  CAS  Google Scholar 

  34. Yazdanian, M., Glynn, S., Wright, J. and Hawi, A., Pharm. Res., 15 (1998) 1490.

    Article  PubMed  CAS  Google Scholar 

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Author information

Author notes

  1. Thomas Österberg

    Present address: Pharmacia & Upjohn AB, Pharmaceutical Development, SE-112 87, Stockholm, Sweden

Authors and Affiliations

  1. Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85, Södertälje, Sweden

    Ulf Norinder

  2. Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85, Södertälje, Sweden

    Thomas Österberg

Authors
  1. Ulf Norinder
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  2. Thomas Österberg
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Correspondence to Ulf Norinder.

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Norinder, U., Österberg, T. The applicability of computational chemistry in the evaluation and prediction of drug transport properties. Perspectives in Drug Discovery and Design 19, 1–18 (2000). https://doi.org/10.1023/A:1008718204115

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