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The Hill equation and the origin of quantitative pharmacology

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Abstract

This review addresses the 100-year-old Hill equation (published in January 22, 1910), the first formula relating the result of a reversible association (e.g., concentration of a complex, magnitude of an effect) to the variable concentration of one of the associating substances (the other being present in a constant and relatively low concentration). In addition, the Hill equation was the first (and is the simplest) quantitative receptor model in pharmacology. Although the Hill equation is an empirical receptor model (its parameters have only physico-chemical meaning for a simple ligand binding reaction), it requires only minor a priori knowledge about the mechanism of action for the investigated agonist to reliably fit concentration-response curve data and to yield useful results (in contrast to most of the advanced receptor models). Thus, the Hill equation has remained an important tool for physiological and pharmacological investigations including drug discovery, moreover it serves as a theoretical basis for the development of new pharmacological models.

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References

  • Black J.W., Leff P. (1983) Operational models of pharmacological agonism. Proceedings of the Royal Society B: Biological Sciences 220: 141–162

    Article  Google Scholar 

  • Clark A.J. (1926) The antagonism of acetylcholine by atropine. Journal of Physiology (London) 61: 547–556

    Google Scholar 

  • Colquhoun D. (1998) Binding, gating, affinity and efficacy: The interpretation of structure-activity relationships for agonists and of the effects of mutating receptors. British Journal of Pharmacology 125: 924–947

    Article  Google Scholar 

  • Colquhoun D. (2006) The quantitative analysis of drug-receptor interactions: A short history. Trends in Pharmacological Sciences 27: 149–157

    Article  Google Scholar 

  • Danhof M., de Jongh J., De Lange E.C., Della Pasqua O., Ploeger B.A., Voskuyl R.A. (2007) Mechanism-based pharmacokinetic-pharmacodynamic modeling: Biophase distribution, receptor theory, and dynamical systems analysis. Annual Review of Pharmacology and Toxicology 47: 357–400

    Article  Google Scholar 

  • Del Castillo J., Katz B. (1957) Interaction at end-plate receptors between different choline derivatives. Proceedings of the Royal Society B: Biological Sciences 146: 369–381

    Article  Google Scholar 

  • Furchgott R.F., Bursztyn P. (1967) Comparison of dissociation constants and of relative efficacies of selected agonists acting on parasympathetic receptors. Annals of the New York Academy of Sciences 144: 882–899

    Article  Google Scholar 

  • Giraldo J., Vivas N.M., Vila E., Badia A. (2002) Assessing the (a)symmetry of concentration-effect curves: Empirical versus mechanistic models. Pharmacol Ther 95: 21–45

    Article  Google Scholar 

  • Goutelle S., Maurin M., Rougier F., Barbaut X., Bourguignon L., Ducher M., Maire P. (2008) The Hill equation: A review of its capabilities in pharmacological modelling. Fundamental and Clinical Pharmacology 22: 633–648

    Article  Google Scholar 

  • Hill A.V. (1909) The mode of action of nicotine and curari, determined by the form of the contraction curve and the method of temperature coefficients. Journal of Physiology (London) 39: 361–373

    Google Scholar 

  • A. V. Hill. 1910. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. Journal of Physiology (London) 40: Proceedings iv–vii.

  • Keller F., Giehl M., Czock D., Zellner D. (2002) PK-PD curve-fitting problems with the Hill equation? Try one of the 1-exp functions derived from Hodgkin, Douglas or Gompertz. International Journal of Clinical Pharmacology and Therapeutics 40: 23–29

    Google Scholar 

  • Kenakin T. (2006) Data-driven analysis in drug discovery. Journal of Receptors and Signal Transduction Research 26: 299–327

    Article  Google Scholar 

  • Kenakin T. (2004) Principles: Receptor theory in pharmacology. Trends in Pharmacological Sciences 25: 186–192

    Article  Google Scholar 

  • Kenakin T. (2009) Quantifying biological activity in chemical terms: A pharmacology primer to describe drug effect. ACS Chemical Biology 4: 249–260

    Article  Google Scholar 

  • Langmuir I. (1918) The adsorption of gases on plane surfaces of glass, mica and platinum. Journal of the American Chemical Society 40: 1361

    Article  Google Scholar 

  • Maehle A.H. (2004) Receptive substances”: John Newport Langley (1852–1925) and his path to a receptor theory of drug action. Medical History 48: 153–174

    Article  Google Scholar 

  • Maehle A.H. (2009) A binding question: The evolution of the receptor concept. Endeavour 33: 135–140

    Article  Google Scholar 

  • Mager D.E., Wyska E., Jusko W.J. (2003) Diversity of mechanism-based pharmacodynamic models. Drug Metabolism and Disposition 31: 510–518

    Article  Google Scholar 

  • Michaelis L., Menten M.L. (1913) Die Kinetik der Intertinwerkung. Biochemische Zeitschrift 49: 333–369

    Google Scholar 

  • Motulsky, H.J., and A. Christopoulos. 2003. Fitting models to biological data using linear and nonlinear regression. A practical guide to curve fitting. Oxford: Oxford Press (Corrected online version: http://www.graphpad.com/manuals/Prism4/RegressionBook.pdf).

  • Neubig R.R., Spedding M., Kenakin T., Christopoulos A. (2003) International union of pharmacology committee on receptor nomenclature and drug classification. XXXVIII. update on terms and symbols in quantitative pharmacology. Pharmacological Reviews 55: 597–606

    Google Scholar 

  • Pelner L. (1972) Corpora non agunt nisi fixata. Maxim behind all of Ehrlich’s great discoveries. New York State Journal of Medicine 72: 620–624

    Google Scholar 

  • Rang, H.P. 2006. The receptor concept: Pharmacology’s big idea. British Journal of Pharmacology 147: S9–16.

    Google Scholar 

  • Richards F.J. (1959) A flexible growth function for empirical use. Journal of Experimental Botany 10: 290–300

    Article  Google Scholar 

  • Ruffolo R.R. Jr. (1982) Review important concepts of receptor theory. Journal of Autonomic Pharmacology 2: 277–295

    Article  Google Scholar 

  • Scheindlin S. (2001) A brief history of pharmacology. Modern Drug Discovery 4: 87–88

    Google Scholar 

  • Stephenson R.P. (1956) A modification of receptor theory. British Journal of Pharmacology 11: 379–393

    Google Scholar 

  • Van der Graaf P.H., Danhof M. (1997) Analysis of drug-receptor interactions in vivo: A new approach in pharmacokinetic-pharmacodynamic modelling. International Journal of Clinical Pharmacology and Therapeutics 35: 442–446

    Google Scholar 

  • Van der Graaf P.H., Schoemaker R.C. (1999) Analysis of asymmetry of agonist concentration-effect curves. Journal of Pharmacological and Toxicological Methods 41: 107–115

    Article  Google Scholar 

  • Van der Graaf P.H., Stam W.B. (1999) Analysis of receptor inactivation experiments with the operational model of agonism yields correlated estimates of agonist affinity and efficacy. Journal of Pharmacological and Toxicological Methods 41: 117–125

    Article  Google Scholar 

  • Weiss J.N. (1997) The Hill equation revisited: Uses and misuses. FASEB Journal 11: 835–841

    Google Scholar 

  • Zimmer, H.G. (1996) Carl Ludwig: the man, his time, his influence. Pflugers Archiv 432: R9–22.

    Google Scholar 

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Correspondence to Rudolf Gesztelyi.

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Communicated by: Manfred Laubichler.

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Gesztelyi, R., Zsuga, J., Kemeny-Beke, A. et al. The Hill equation and the origin of quantitative pharmacology. Arch. Hist. Exact Sci. 66, 427–438 (2012). https://doi.org/10.1007/s00407-012-0098-5

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