Abstract
In this review, we first examine the contextual background of structure–pharmacokinetic relationships. Some concepts in drug disposition are briefly recalled, and inherent difficulties instructure–pharmacokinetic relationships are outlined. Lipophilicity is then investigated in the light of the intermolecular and intramolecular interactions it encodes. In the main body of the review, a number of pharmacokinetic processes are examined for their relations with lipophilicity. These processes are taken in a logical sequence of permeation, absorption (intestine, skin, cornea, brain), plasma protein binding, tissue distribution, volume of distribution and renal clearance. Relations between metabolism and lipophilicity are more complex, since biotransformation involves both low-energy (enzyme binding) and high-energy (catalysis) processes. Only the former may be related to lipophilicity. The conclusion argues against faulty statistics and over-interpretation.
Similar content being viewed by others
References
Testa, B., In Testa, B. (Ed.) Advances in Drug Research, Vol. 13, Academic Press, London, 1984, pp. 1–58.
Testa, B., Trends Pharmacol. Sci., 8 (1987) 381.
Testa, B., In Wolff, M.E. (Ed.) Burger's Medicinal Chemistry and Drug Discovery, Vol. 1, 5th ed., Wiley-Interscience, New York, NY, 1995, pp. 129–180.
Wermuth, C.G. and Testa, B., In Wermuth, C.G. (Ed.) The Practice of Medicinal Chemistry, Academic Press, London, 1996, pp. 615–641.
Arië ns, E.J., Farmaco, 24 (1966) 3.
Lien, E.J., Annu. Rev. Pharmacol. Toxicol., 21 (1981) 31.
Seydel, J.K. and Schaper, K.J., Pharmacol. Ther., 15 (1982) 131.
Austel, V. and Kutter, E., In Topliss, J.G. (Ed.) Quantitative Structure-Activity Relationships of Drugs, Academic Press, London, 1983, pp. 437–496.
Seydel, J.K., In Dearden, J.C. (Ed.) Quantitative Approaches to Drug Design, Elsevier, Amsterdam, 1983, pp. 163–181.
Mayer, J.M. and van de Waterbeemd, H., Environ. Health Perspect., 61 (1985) 295.
Testa, B. and Mayer, J.M., Acta Pharm. Jugosl., 40 (1990) 315.
Smith, D.A., Jones, B.C. and Walker, D.K., Med. Res. Rev., 16 (1996) 243.
Testa, B., Kier, L.B. and Carrupt, P.A., Med. Res. Rev., 17 (1997) 303.
Testa, B., Med. Chem. Res., 7 (1997) 340.
Levy, R.H. and Boddy, A.V., Pharm. Res., 8 (1991) 551.
Testa, B. and Caldwell, J., Med. Res. Rev., 16 (1996) 233.
Taylor, R.C., Pownall, R. and Burke, W., J. Pharm. Pharmacol., 37 (1985) 280.
Woods, P.B. and Robinson, M.L., J. Pharm. Pharmacol., 33 (1981) 172.
Cruickshank, J.M., Int. J. Clin. Pharmacol. Res., 2 (1982) 185.
Helmer, F., Kiehs, K. and Hansch, C., Biochemistry, 7 (1968) 2858.
Hansch, C. and Leo, A., Substituent Constants for Correlation Analysis in Chemistry and Biology, John Wiley & Sons, New York, NY, 1979.
Rekker, R.F., The Hydrophobic Fragmental Constant, Elsevier, Amsterdam, 1977.
Testa, B. and Kier, L.B., Med. Res. Rev., 11 (1991) 35.
Testa, B., Carrupt, P.A., Gaillard, P., Billois, F. and Weber, P., Pharm. Res., 13 (1996) 335.
Testa, B., Carrupt, P.A., Gaillard, P. and Tsai, R.S., In Pliska, V., Testa, B. and van de Waterbeemd, H. (Eds.) Lipophilicity in Drug Action and Toxicology, VCH Publishers, Weinheim, 1996, pp. 49–71.
van de Waterbeemd, H. and Testa, B., In Testa, B. (Ed.) Advances in Drug Research, Vol. 16, Academic Press, London, 1987, pp. 87–227.
El Tayar, N., Testa, B. and Carrupt, P.A., J. Phys. Chem., 96 (1992) 1455.
Taft, R.W., Abboud, J.L.M., Kamlet, M.J. and Abraham, M.H., J. Sol. Chem., 14 (1985) 153.
El Tayar, N., Tsai, R.S., Testa, B., Carrupt, P.A. and Leo, A., J. Pharm. Sci., 80 (1991) 590.
Rogers, J.A. and Choi, Y.W., Pharm. Res., 10 (1993) 913.
Balon, K., Riebesehl, B.U. and Müller, B.W., Pharm. Res., 16 (1999) 882.
Beigi, F., Gottschalk, I., Lagerquist Hägglund, C., Haneskog, L., Brekkan, E., Osterberg, T. and Lundhal, P., Int. J. Pharm., 164 (1998) 129.
Ducarme, A., Neuwels, M., Goldstein, S. and Massingham, R., Eur. J. Med. Chem., 33 (1998) 215.
Reichel, A. and Begley, D.J., Pharm. Res., 15 (1998) 1270.
Alvarez, F.M., Bottom, C.B., Chikhale, P. and Pidgeon, C., In Ngo, T.T. (Ed.) Molecular Interactions in Bioseparations, Plenum Press, New York, NY, 1993, pp. 151–167.
Rekker, R.F. and De Kort, H.M., Eur. J. Med. Chem., 14 (1979) 479.
Hansch, C. and Anderson, S.M., J. Org. Chem., 32 (1967) 2583.
Wiley, R.A. and Rich, D.H., Med. Res. Rev., 13 (1993) 327.
Rich, D.H., In Testa, B., Kyburz, E., Fuhrer, W. and Giger, R. (Eds.) Perspectives in Medicinal Chemistry, VCH Publishers, Weinheim, 1993, pp. 15–25.
Jiang, X.K., Acc. Chem. Res., 21 (1988) 362.
Carrupt, P.A., Testa, B., Bechalany, A., El Tayar, N., Descas, P. and Perrissoud, D., J. Med. Chem., 34 (1991) 1272.
Caron, G., Reymond, F., Carrupt, P.A., Girault, H.H. and Testa, B., Pharm. Sci. Technol. Today, 2 (1999) 327.
Leahy, D.E., Taylor, P.J. and Wait, A.R., Quant. Struct.-Act. Relat., 8 (1989) 17.
Pagliara, A., Caron, G., Lisa, G., Fan, W., Gaillard, P., Carrupt, P.A., Testa, B. and Abraham, M.H., J. Chem. Soc., Perkin Trans. 2, (1997) 2639.
Steyaert, G., Lisa, G., Gaillard, P., Boss, G., Reymond, F., Girault, H.H., Carrupt, P.A. and Testa, B., J. Chem. Soc., Faraday Trans., 93 (1997) 401.
Abraham, M.H., Chadha, H.S., Whiting, G.S. and Mitchell, R.C., J. Pharm. Sci., 83 (1994) 1085.
Young, R.C., Mitchell, R.C., Brown, T.H., Ganellin, C.R., Griffiths, R., Jones, M., Rana, K.K., Saunders, D., Smith, I.R., Sore, N.E. and Wilks, T.J., J. Med. Chem., 31 (1988) 656.
El Tayar, N., Tsai, R.S., Testa, B., Carrupt, P.A., Hansch, C. and Leo, A., J. Pharm. Sci., 80 (1991) 744.
Abraham, M.H., Chadha, H.S. and Mitchell, R.C., J. Pharm. Sci., 83 (1994) 1257.
von Geldern, T.W., Hoffman, D.J., Kester, J.A., Nellans, H.N., Dayton, B.D., Calzadilla, S.V., Marsh, K.C., Hernandez, L., Chiou, W., Dixon, D.B., Wu-Wong, J.R. and Opgenorth, T.J., J. Med. Chem., 39 (1996) 982.
Yoshida, F. and Topliss, J.G., J. Pharm. Sci., 85 (1996) 819.
Caron, G., Pagliara, A., Carrupt, P.A., Gaillard, P. and Testa, B., Helv. Chim. Acta, 79 (1996) 1683.
Caron, G., Carrupt, P.A., Testa, B., Ermondi, G. and Gasco, A., Pharm. Res., 13 (1996) 1186.
Pagliara, A., Testa, B., Carrupt, P.A., Jolliet, P., Morin, C., Morin, D., Urien, S., Tillement, J.P. and Rihoux, J.P., J. Med. Chem., 41 (1998) 853.
Carrupt, P.A., Testa, B. and Gaillard, P., In Boyd, D.B. and Lipkowitz, K.B. (Eds.) Reviews in Computational Chemistry, Vol. 11, Wiley-VCH, New York, NY, 1997, pp. 241–315.
Caron, G., Gaillard, P., Carrupt, P.A. and Testa, B., Helv. Chim. Acta, 80 (1997) 449.
Kubinyi, H., QSAR: Hansch Analysis and Related Approaches, VCH Publishers, Weinheim, 1993.
Murthy, K.S. and Zograti, G., J. Pharm. Sci., 59 (1970) 1281.
Reymond, F., Carrupt, P.A., Testa, B. and Girault, H.H., Chem. Eur. J., 5 (1999) 39.
Tsai, R.S., Testa, B., El Tayar, N. and Carrupt, P.A., J. Chem. Soc., Perkin Trans. 2, (1991) 1797.
Takacs-Novak, K., Jozan, M. and Szasz, G., Int. J. Pharm., 113 (1995) 47.
Hatanaka, T., Morigaki, S., Aiba, T., Katayama, K. and Koizumi, T., Int. J. Pharm., 125 (1995) 195.
Abraham, M.H., Takacs-Novak, K. and Mitchell, R.C., J. Pharm. Sci., 86 (1997) 310.
Pagliara, A., Carrupt, P.A., Caron, G., Gaillard, P. and Testa, B., Chem. Rev., 97 (1997) 3385.
van de Waterbeemd, H. and Kansy, M., Chimia, 46 (1992) 299.
Ren, S., Das, A. and Lien, E.J., J. Drug Targeting, 4 (1996) 103.
Artursson, P., Palm, K. and Luthman, K., Adv. Drug Deliv. Rev., 22 (1996) 67.
Irvine, J.D., Takahashi, L., Lockhart, K., Cheong, J., Tolan, J.W., Selick, H.E. and Grove, R., J. Pharm. Sci., 88 (1999) 28.
Burton, P.S., Conradi, R.A., Ho, N.F.H., Hilgers, A.R. and Borchardt, R.T., J. Pharm. Sci., 85 (1996) 1336.
Buur, A., Trier, L., Magnusson, C. and Artursson, P., Int. J. Pharm., 129 (1996) 223.
Lennernas, H., J. Pharm. Sci., 87 (1998) 403.
Norinder, U., Osterberg, T. and Artursson, P., Pharm. Res., 14 (1997) 1786.
Plá-Delfina, J.M. and Moreno, J., J. Pharmacokinet. Biopharm., 9 (1981) 191.
Yoshimura, Y. and Kakeya, N., Int. J. Pharm., 17 (1983) 47.
Palm, K., Luthman, K., Ungell, A.L., Strandlund, G., Beigi, F., Lundhal, P. and Artursson, P., J. Med. Chem., 41 (1998) 5382.
Breitkreutz, J., Pharm. Res., 15 (1998) 1370.
Norinder, U., Osterberg, T. and Artursson, P., Eur. J. Pharm. Sci., 8 (1999) 49.
Krarup, L.H., Christensen, I.T., Hovgaard, L. and Frokjaer, S., Pharm. Res., 15 (1998) 972.
Clark, D.E., J. Pharm. Sci., 88 (1999) 807.
Clark, D.E., J. Pharm. Sci., 88 (1999) 815.
Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J., Adv. Drug Deliv. Rev., 23 (1997) 3.
Guy, R.H. and Potts, R.O., J. Pharm. Sci., 81 (1992) 603.
Potts, R.O. and Guy, R.H., Pharm. Res., 12 (1995) 1628.
Ridout, G., Houk, J., Guy, R.H., Santus, G.C., Hadgraft, J. and Hall, L.L., Farmaco, 47 (1992) 869.
Ackerman, C., Flynn, G.L. and Smith, W.M., Int. J. Pharm., 36 (1987) 67.
Potts, R.O. and Guy, R.H., Pharm. Res., 10 (1993) 635.
Singh, P. and Roberts, M.S., J. Pharmacol. Exp. Ther., 268 (1984) 144.
Schoenwald, R. and Huang, H.S., J. Pharm. Sci., 72 (1983) 1266.
Begley, D.J., J. Pharm. Pharmacol., 48 (1996) 136.
Hansch, C. and Clayton, J.M., J. Pharm. Sci., 62 (1973) 1.
Hansch, C., Björkroth, J.P. and Leo, A., J. Pharm. Sci., 76 (1987) 663.
Dischino, D.D., Welch, M.J., Kilbourn, M.R. and Raichle, M.E., J. Nucl. Med., 24 (1983) 1030.
van Bree, J.B.M.M., de Boer, A.G., Danhof, M., Ginsel, L.A. and Breimer, D.D., J. Pharmacol. Exp. Ther., 247 (1988) 1233.
Jaehde, U., Goto, T., de Boer, A.G. and Breimer, D.D.B., Eur. J. Pharm. Sci., 1 (1993) 49.
Levin, V.A., J. Med. Chem., 23 (1980) 682.
Rim, S., Audus, K.L. and Borchardt, R.T., Int. J. Pharm., 32 (1986) 79.
Chikhale, E.G., Ng, K.Y., Burton, P.S. and Borchardt, R.T., Pharm. Res., 11 (1994) 412.
ter Laak, A.M., Tsai, R.S., Donné-op den Kelder, G.M., Carrupt, P.A., Testa, B. and Timmerman, H., Eur. J. Pharm. Sci., 2 (1994) 373.
Rodrigues de Miranda, J.F., Eikelboom, T.D. and van Os, G.A.J., Mol. Pharmacol., 12 (1976) 454.
Kaibara, A., Hirose, M. and Nakagawa, T., Chem. Pharm. Bull., 39 (1991) 720.
Láznicek, M., Kvetina, J., Mazák, J. and Krch, V., J. Pharm. Pharmacol., 39 (1987) 79.
Demotes-Mainard Péhourcq, F., Radouane, A., Labat, L. and Bannwarth, B., Pharm. Res., 12 (1995) 1535.
Hervé, F., Caron, G., Duché, J.C., Gaillard, P., Abd Rahman, N., Tsantili-Kakoulidou, A., Carrupt, P.A., d'Athis, P., Tillement, J.P. and Testa, B., Mol. Pharmacol., 54 (1998) 129.
Janssen, L.H.M. and Perrin, J.H., Eur. J. Med. Chem., 11 (1976) 389.
Urien, S., Giroud, Y., Tsai, R.S., Carrupt, P.A., Brée, F., Testa, B. and Tillement, J.P., Biochem. J., 306 (1995) 545.
Fichtl, B., Nieciecki, A.V. and Walter, K., In Testa, B. (Ed.) Advances in Drug Research, Vol. 20, Academic Press, London, 1991, pp. 117–166.
Bickel, M.H., In Testa, B. and Meyer, U.A. (Eds.) Advances in Drug Research, Vol. 25, Academic Press, London, 1994, pp. 55–86.
Cheymol, G., Poirier, J.M., Carrupt, P.A., Testa, B., Weissenburger, J., Levron, J.C. and Snoeck, E., Brit. J. Clin. Pharmacol., 43 (1997) 563.
Yoshida, H., Okumura, K., Kamiya, A. and Hori, R., Chem. Pharm. Bull., 37 (1989) 450.
Okumura, K., Yoshida, K., Kamiya, A. and Hori, R., Chem. Pharm. Bull., 37 (1989) 1109.
Yokogawa, K., Nakashima, E., Ishizaki, J., Maeda, H., Nagano, T. and Ichimura, F., Pharm. Res., 7 (1990) 691.
Byard, J.L. and Goldberg, L., Food Cosmet. Toxicol., 11 (1973) 391.
Ball, L.M., Renwick, A.G. and Williams, R.T., Xenobiotica, 7 (1977) 189.
Ashton, M.J., Clark, B., Jones, K.M., Moss, G.F., Neale, M.G. and Ritchie, J.T., Toxicol. Appl. Pharmacol., 26 (1973) 319.
Lachmann, G., Siegemund, B. and Kusche, W., Arzneim.-Forsch., 40 (1990) 200.
Smith, D.A., Brown, K. and Neale, M.G., Drug Metab. Rev., 16 (1985) 365.
Gonzalez, F.J. and Nebert, D.W., Trends Genet., 6 (1990) 9.
Bickel, M.H., Experientia, Suppl., 38 (1982) 879.
Jondorf, W.R., Veterinary Res. Commun., 7 (1983) 277.
Testa, B., Acta Pharm. Nord., 2 (1990) 137.
Testa, B., Chirality, 1 (1989) 7.
Durrer, A., Walther, B., Racciatti, A., Boss, G. and Testa, B., Pharm. Res., 8 (1991) 832.
Martin, Y.C. and Hansch, C., J. Med. Chem., 14 (1971) 777.
Hansch, C., Drug Metab. Rev., 1 (1972) 1.
Yu, P.H., J. Pharm. Pharmacol., 41 (1989) 205.
Yu, P.H., J. Pharm. Pharmacol., 42 (1990) 882.
Morgenstern, R., Lundqvist, G., Hancock, V. and DePierre, J.W., J. Biol. Chem., 263 (1988) 6671.
Testa, B., The Metabolism of Drugs and Other Xenobiotics. Biochemistry of Redox Reactions, Academic Press, London, 1995.
Al-Gailany, K.A.S., Houston, J.B. and Bridges, J.W., Biochem. Pharmacol., 27 (1978) 783.
Backes, W.L. and Canady, W.J., Pharmacol. Ther., 12 (1981) 133.
Backes, W.L., Hogaboom, M. and Canady, W.J., J. Biol. Chem., 257 (1982) 4063.
Backes, W.L., Cawley, G., Eyer, C.S., Means, M., Causey, K.M. and Canady, W.J., Arch. Biochem. Biophys., 304 (1993) 27.
Walther, B., Vis, P. and Taylor, A., In Pliska, V., Testa, B. and van de Waterbeemd, H. (Eds.) Lipophilicity in Drug Action and Toxicology, VCH Publishers, Weinheim, 1996, pp. 253–261.
Fears, R., Prog. Lip. Res., 24 (1986) 177.
Giroud, Y., Carrupt, P.A., Pagliara, A., Testa, B. and Dickinson, R.G., Helv. Chim. Acta, 81 (1998) 330.
Caron, G., Ermondi, G., Boschi, D., Carrupt, P.A., Fruttero, R., Testa, B. and Gasco, A., Helv. Chim. Acta, 82 (1999) 1630.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Testa, B., Crivori, P., Reist, M. et al. The influence of lipophilicity on the pharmacokinetic behavior of drugs: Concepts and examples. Perspectives in Drug Discovery and Design 19, 179–211 (2000). https://doi.org/10.1023/A:1008741731244
Issue Date:
DOI: https://doi.org/10.1023/A:1008741731244