Advertisement

Journal of Computer-Aided Molecular Design

, Volume 15, Issue 3, pp 273–286 | Cite as

Lipophilicity in PK design: methyl, ethyl, futile

  • Han van de Waterbeemd
  • Dennis A. Smith
  • Barry C. Jones
Article

Abstract

Lipophilicity, often expressed as distribution coefficients (log D) in octanol/water, is an important physicochemical parameter influencing processes such as oral absorption, brain uptake and various pharmacokinetic (PK) properties. Increasing log D values increases oral absorption, plasma protein binding and volume of distribution. However, more lipophilic compounds also become more vulnerable to P450 metabolism, leading to higher clearance. Molecular size and hydrogen bonding capacity are two other properties often considered as important for membrane permeation and pharmacokinetics. Interrelationships among these physicochemical properties are discussed. Increasing size (molecular weight) often gives higher potency, but inevitably also leads to either higher lipophilicity, and hence poorer dissolution/solubility, or to more hydrogen bonding capacity, which limits oral absorption. Differences in optimal properties between gastrointestinal absorption and uptake into the brain are addressed. Special attention is given to the desired lipophilicity of CNS drugs. In examples using β-blockers, Ca channel antagonists and peptidic renin inhibitors we will demonstrate how potency and pharmacokinetic properties need to be balanced.

β-adrenoceptor antagonists calcium channel antagonists clearance hydrophobicity lipophilicity P450 metabolism P-glycoprotein plasma protein binding renin inhibitors volume of distribution 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Smith, D.A., Jones, B.C. and Walker, D.K., Med. Res. Rev., 16 (1996) 243-266.Google Scholar
  2. 2.
    Van de Waterbeemd, H., Carter, R.E., Grassy, G., Kubinyi, H., Martin, Y.C., Tute, M.S. and Willett, P., Pure Appl. Chem., 69 (1997) 1137-1152.Google Scholar
  3. 3.
    Pliska, V., Testa, B. and Van de Waterbeemd, H. (Eds.), Lipophilicity in Drug Action and Toxicology, VCH, Weinheim, 1996.Google Scholar
  4. 4.
    Smith, D.A., In Van de Waterbeemd, H., Testa, B. and Folkers, G. (Eds.), Computer-Assisted Lead Finding and Optimization, Wiley-VCH, Weinheim, 1997, pp. 267-276.Google Scholar
  5. 5.
    Wacher, V.J., Salphati, L. and Benet, L.Z., Adv. Drug Deliv. Rev., 20 (1996) 99-112.Google Scholar
  6. 6.
    Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J., Adv. Drug Del. Res., 23 (1997) 3-25.Google Scholar
  7. 7.
    Yee, S.H., Pharm. Res., 14 (1997) 763-766.Google Scholar
  8. 8.
    Van de Waterbeemd, H., in Dressman, J. (Ed.), Methods for Assessing Oral Drug Absorption, Dekker, New York, NY 2000, pp. 31-49.Google Scholar
  9. 9.
    Camenisch, G., Alsenz, J., Van de Waterbeemd, H. and Folkers, G., Eur. J. Pharm. Sci., 6 (1998) 313-319.Google Scholar
  10. 10.
    Van de Waterbeemd, H., Eur. J. Pharm. Sci. 7 (1998) 1-3.Google Scholar
  11. 11.
    Van de Waterbeemd, H. and Kansy, M., Chimia, 46 (1992) 299-303.Google Scholar
  12. 12.
    Palm, K., Luthman, K., Ungell, A.-L., Strandlund, G. and Artursson, P., J. Pharm. Sci., 85 (1996) 32-39.Google Scholar
  13. 13.
    Van de Waterbeemd, H., Camenisch, G., Folkers, G. and Raevsky, O.A., Quant. Struct. Act. Relat., 15 (1996) 480-490.Google Scholar
  14. 14.
    Palm, K., Luthman, K., Ungell, A.-L., Strandlund, G., Beigi, F., Lundahl, P. and Artursson, P., J. Med. Chem., 41 (1998) 5382-5392.Google Scholar
  15. 15.
    Palm, K., Stenberg, P., Luthman, K. and Artursson, P., Pharm. Res., 14 (1997) 568-571.Google Scholar
  16. 16.
    Kansy, M., Senner, F. and Gubernator, K., J. Med. Chem., 41 (1998) 1007-1010.Google Scholar
  17. 17.
    Norinder, U., Österberg, T. and Artursson, P., Pharm. Res., 14 (1997) 1786-1791.Google Scholar
  18. 18.
    Winiwarter, S., Bonham, N.M., Ax, F., Hallberg, A. and Karlén, A., J. Med. Chem., 41 (1998) 4939-4949.Google Scholar
  19. 19.
    Gupta, S.P., Chem. Rev., 89 (1989) 1765-1800.Google Scholar
  20. 20.
    Van de Waterbeemd, H., Camenisch, G., Folkers, G., Chrétien, J.R. and Raevsky, O.A., J. Drug Target., 6 (1999) 151-165.Google Scholar
  21. 21.
    Fischer, H., Gottschlich, R. and Seelig, A., J. Membr. Biol., 165 (1998) 201-211.Google Scholar
  22. 22.
    Young, R.C., Mitchell, R.C., Brown, T.H., Ganellin, C.R., Griffith, R., Jones, M., Rana, K.K., Saunders, D., Smith, I.R., Sore, N.E. and Wilks, T.J., J. Med. Chem., 31 (1988) 656-671.Google Scholar
  23. 23.
    Lombardo, F., Blake, J.F. and Curatolo, W.J., J. Med. Chem., 39 (1996) 4750-4755.Google Scholar
  24. 24.
    Norinder, U., Sjöberg, P. and Österberg, T., J. Pharm. Sci., 87 (1998) 952-959.Google Scholar
  25. 25.
    Luco, J.M., J. Chem. Inf. Comput. Sci., 39 (1999) 396-404.Google Scholar
  26. 26.
    Rowley, M., Kulagowski, J.J., Watt, A.P., Rathbone, D., Stevenson, G.I., Carling, R.W., Baker, R., Marshall, G.R., Kemp, J.a., Foster, A.C., Grimwood, S., Hargreaves, R., Hurley, C., Saywell, K.L., Tricklebank, M.D. and Leeson, P.D., J. Med. Chem., 40 (1997) 4053-4068.Google Scholar
  27. 27.
    Van Asperen, J., Mayer, U., Van Tellingen, O. and Beijen, J.H., J. Pharm. Sci., 86 (1997) 881-884.Google Scholar
  28. 28.
    Yamada, Y., Ito, K., Nakamura, K., Sawada, Y. and Iga, T., Biol. Pharm. Bull., 16 (1993) 1251-1259.Google Scholar
  29. 29.
    Meir, J., Am. Heart J., 104 (1982) 364-373.Google Scholar
  30. 30.
    Hinderling, P.H., Schmidlin, O. and Seydel, J.K., J Bioharm Pharmacokinet., 2 (1984) 263-286.Google Scholar
  31. 31.
    Smith, D.A., Ackland, M.J. and Jones, B.C., Drug Disc. Today, 2 (1997) 406-414.Google Scholar
  32. 32.
    Smith, D.A., Ackland, M.J. and Jones, B.C., Drug Disc. Today, 2 (1997) 479-486.Google Scholar
  33. 33.
    Smith, D.A. and Jones, B., Drug Discov. Dev., 2 (1999) 33-41.Google Scholar
  34. 34.
    Ferrari, S., Leemann, T. and Dayer, P., Life Sci., 48 (1991) 2259-2265.Google Scholar
  35. 35.
    Spahn-Langguth, H., Baktir, G., Radschuweit, A., Okyar, A., Terhaag, B., Ader, P., Hanafy, A. and Langguth, P., Int. J. Clin. Pharm. Thev., 36 (1998) 16-24.Google Scholar
  36. 36.
    Hamilton, H.W., Steinbaugh, B.A., Stewart, B.H., Chan, O.H., Schmid, H.L., Schroeder, R., Ryan, M.J., Keiser, J., Taylor, M.D., Blankley, C.J., Kaltenbronn, J.S. Wright, J. and Hicks, J., J. Med. Chem., 38 (1995) 1446-1435.Google Scholar
  37. 37.
    Chan, O.H. and Stewart, B.H., Drug Discov. Today, 1 (1996) 461-473.Google Scholar
  38. 38.
    Rosenberg, S.H. and Kleinert, H.D., In Borchardt, R.T., Freidinger, R.M., Sawyer, T.K. and Smith, P.L. (Eds.) Integration of Pharmaceutical Discovery and Development. Case Histories, Plenum Press, New York, 1998, pp. 7-28.Google Scholar
  39. 39.
    Hilgert, M., Noldner, M., Chatterjee, S.S. and Klein, J. (1999) Neurosci. Lett., 263 (1999) 193-196.Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Han van de Waterbeemd
    • 1
  • Dennis A. Smith
    • 1
  • Barry C. Jones
    • 1
  1. 1.Sandwich Laboratories, Department of Drug MetabolismPfizer Global Research and DevelopmentSandwich, KentUK

Personalised recommendations