Pharmaceutical Research

, Volume 19, Issue 8, pp 1150–1159 | Cite as

Theoretical and Experimental Exploration of the Lipophilicity of Zwitterionic Drugs in the 1,2-Dichloroethane/Water System

  • Géraldine Bouchard
  • Alessandra Pagliara
  • Pierre-Alain Carrupt
  • Bernard Testa
  • Véronique Gobry
  • Hubert H. Girault
Article

Abstract

Purpose. This work examines the lipophilic behavior of various zwitterions and shows how distribution profiles in biphasic systems and ionic partition diagrams may improve our understanding of pH-absorption profiles of drugs.

Methods. The lipophilicity of various zwitterionic drugs was examined by potentiometry and cyclic voltammetry in the 1,2-dichloroethane/water system to study the intramolecular interactions and conformational effects affecting absorption and activity of zwitterions, as well as to draw their theoretical and experimental ionic partition diagrams.

Results. Different theoretical partition diagrams are reported according to the tautomeric constant of the zwitterion. Shifts of apparent pKa are obtained in the ionic partition diagrams of raclopride and eticlopride and compared to the deviations from pH-absorption profile described in the literature for lipophilic drugs. The physicochemical origin of these shifts is discussed.

Conclusions. The comparison between pH-absorption profiles and ionic partition diagrams of zwitterions is shown here to be of value for a better mechanistic understanding of absorption processes, thus opening new perspectives in studying pH-absorption profiles of ionizable drugs.

cyclic voltammetry 1,2-dichloroethane lipophilicity pH-absorption profiles zwitterions 

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REFERENCES

  1. 1.
    A. Pagliara, P.-A. Carrupt, G. Caron, P. Gaillard, and B. Testa. Lipophilicity profiles of ampholytes. Chem. Rev. 97:3385–3400 (1997).Google Scholar
  2. 2.
    G. Caron, F. Reymond, P.-A. Carrupt, H. H. Girault, and B. Testa. Combined molecular lipophilicity descriptors and their role in understanding intramolecular effects. Pharm. Sci. Technol. Today 2:327–335 (1999).Google Scholar
  3. 3.
    G. Bouchard, A. Pagliara, G. Plemper van Balen, P.-A. Carrupt, B. Testa, V. Gobry, H. H. Girault, G. Caron, G. Ermondi, and R. Fruttero. Ionic partition diagram of the zwitterionic antihistamine cetirizine. Helv. Chim. Acta 84:375–387 (2000).Google Scholar
  4. 4.
    A. Albert and E. P. Serjeant. The Determination of Ionization Constants. A Laboratory Manual. Chapman and Hall, London, 1984.Google Scholar
  5. 5.
    J. Wang and R. J. Boyd. Tautomeric equilibria of hydroxypyridines in different solvents: an ab initio study. J. Phys. Chem. 100:16141–16146 (1996).Google Scholar
  6. 6.
    K. Takács-Novák and K. Y. Tam. Multiwavelength spectrophotometric determination of acid dissociation constants-Part V: Microconstants and tautomeric ratios of diprotic amphoteric drugs. J. Pharm. Biomed. Anal. 21:1171–1182 (2000).Google Scholar
  7. 7.
    R. S. Tsai, P.-A. Carrupt, B. Testa, P. Gaillard, N. El Tayar, and T. Hoegberg. Effects of solvation on the ionization and conformation of raclopride and other antidopaminergic 6-methoxysalicylamides: insight into the pharmacophore. J. Med. Chem. 36:196–204 (1993).Google Scholar
  8. 8.
    R. Bonaccorsi, P. Palla, and J. Tomasi. Conformational energy of glycine in aqueous solutions and relative stability of the zwitterionic and neutral forms. An ab initio study. J. Am. Chem. Soc. 106:1945–1950 (1984).Google Scholar
  9. 9.
    F. R. Tortonda, J. L. Pascual-Ahuir, E. Silla, and I. Tunon. Why is glycine a zwitterion in aqueous solution? A theoretical study of solvent stabilizing factors. Chem. Phys. Lett. 260:21–26 (1996).Google Scholar
  10. 10.
    N. E. Hal and B. J. Smith. Solvation effects on zwitterion formation. J. Phys. Chem. A 102:3985–3990 (1998).Google Scholar
  11. 11.
    F. Reymond, G. Steyaert, P.-A. Carrupt, B. Testa, and H. H. Girault. Ionic partition diagrams: a potential-pH representation. J. Am. Chem. Soc. 118:11951–11957 (1996).Google Scholar
  12. 12.
    1,2-Dichloroethane (Environmental Health Criteria N° 176). World Health Organization, Geneva, 1995.Google Scholar
  13. 13.
    V. Gobry, G. Bouchard, P.-A. Carrupt, B. Testa, and H. H. Girault. Physicochemical characterization of sildenafil: ionization, lipophilicity behavior, and ionic-partition diagram studied by two-phase titration and electrochemistry. Helv. Chim. Acta 83:1465–1474 (2000).Google Scholar
  14. 14.
    K. Takács-Novák, J. Kökösi, B. Podanyi, B. Noszal, R. S. Tsai, G. Lisa, P.-A. Carrupt, and B. Testa. Microscopic protonation/deprotonation equilibria of the anti-inflammatory agent piroxicam. Helv. Chim. Acta 78:553–562 (1995).Google Scholar
  15. 15.
    CLIP1.0. Institute of Medicinal Chemistry, University of Lausanne, 1996.Google Scholar
  16. 16.
    P.-A. Carrupt, P. Gaillard, F. Billois, P. Weber, B. Testa, C. Meyer, and S. Pérez. The molecular lipophilicity potential (MLP): a new tool for log P calculations and docking, and in comparative molecular field analysis (CoMFA). In V. Pliska, B. Testa, and H. van de Waterbeemd (eds.), Lipophilicity in Drug Action and Toxicology, Vol. VCH Publishers, Weinheim, 1996, pp. 195–217.Google Scholar
  17. 17.
    G. Caron, A. Pagliara, P.-A. Carrupt, P. Gaillard, and B. Testa. Physicochemical properties of the anti-inflammatory drug azapropazone. Helv. Chim. Acta 79:1683–1685 (1996).Google Scholar
  18. 18.
    A. Pagliara, B. Testa, P.-A. Carrupt, P. Jolliet, C. Morin, D. Morin, S. Urien, J. P. Tillement, and J. P. Rihoux. Molecular structure and pharmacokinetic behavior of cetirizine, a zwitterionic antihistamine. J. Med. Chem. 41:853–863 (1998).Google Scholar
  19. 19.
    E. H. Gold, W. Chang, M. Cohen, T. Baum, S. Ehrreich, G. Johnson, N. Prioli, and E. J. Sybertz. Synthesis and comparison of some cardiovascular properties of the stereoisomers of labetalol. J. Med. Chem. 25:1363–1370 (1982).Google Scholar
  20. 20.
    G. Steyaert, G. Lisa, P. Gaillard, G. Boss, F. Reymond, H. H. Girault, P.-A. Carrupt, and B. Testa. Intermolecular forces expressed in 1,2-dichloroethane/water partition coefficient: a solvatochromic analysis. J. Chem. Soc. Faraday Trans. 93:401–406 (1997).Google Scholar
  21. 21.
    D. A. Y. L. I. G. H. T. Software. 4.41. Daylight Chemical Information System, Inc., Irvine, California, 1995.Google Scholar
  22. 22.
    F. Reymond, P.-A. Carrupt, B. Testa, and H. H. Girault. Charge and delocalisation effects on the lipophilicity of protonable drugs. Chem. Eur. J. 5:39–47 (1999).Google Scholar
  23. 23.
    R. S. Tsai, P.-A. Carrupt, N. El Tayar, B. Testa, Y. Giroud, P. Andrade, F. Brée, and J. P. Tillement. Physicochemical and structural properties of non-steroidal antiinflammatory oxicams. Helv. Chim. Acta 76:842–854 (1993).Google Scholar
  24. 24.
    A. Tsuji, E. Miyamoto, N. Hashimoto, and T. Yamana. GI absorption of β-lactam antibiotics II: deviation from pH-partitioning hypothesis in penicillin absorption through in situ and in vitro lipoidal barriers. J. Pharm. Sci. 67:1705–1711 (1978).Google Scholar
  25. 25.
    L. S. Schanker. On the mechanism of absorption of drugs from the gastrointestinal tract. J. Med. Pharmac. Chem. 2:343–359 (1960).Google Scholar
  26. 26.
    D. Winne. Shifts of pH-absorption curves. J. Pharmacokin. Biopharm. 5:53–94 (1977).Google Scholar
  27. 27.
    D. Winne. Deviations of intestinal drug absorption from the pH-partition theory. Acta Pharm. Technol. 33:53–59 (1987).Google Scholar
  28. 28.
    H. Kubinyi. QSAR: Hansch Analysis and Related Approaches. VCH Publishers, Weinheim, 1993.Google Scholar
  29. 29.
    V. Gobry, S. Ulmeanu, F. Reymond, G. Bouchard, P.-A. Carrupt, B. Testa, and H. H. Girault. Generalisation of ionic partition diagrams to lipophilic compounds and to biphasic systems with variable volume ratio. J. Am. Chem. Soc. 123:10684–10690 (2001).Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Géraldine Bouchard
  • Alessandra Pagliara
  • Pierre-Alain Carrupt
  • Bernard Testa
  • Véronique Gobry
  • Hubert H. Girault

There are no affiliations available

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