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Scaling of antipyrine intrinsic clearance of unbound drug in 15 mammalian species

European Journal of Drug Metabolism and Pharmacokinetics volume 9, pages 177–183 (1984)Cite this article

Summary

The intrinsic clearance of unbound drug (CLuint) for antipyrine in 15 mammalian species was characterized by an equation of the form, CLuint=ϕ1 (body weight)ϕ 2 (brain weight)ϕ 3, where thetas are constants. Maximum lifespan potential in mammals can also be characterized by an equation of this form. It is suggested that the set of genetic mechanisms regulating longevity and other constitutional characteristics in species is also linked to rates of drug metabolism. The ability to scale interspecies data in pharmacokinetics is taken as an expression of this design principle.

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References

  1. Kuhn, T.S. (1977). Second thoughts on paradigms. In “The Structure of Scientific Theories,” (F. Suppe, ed.) University of Illinois Press, Urbana, pp. 459–517.

    Google Scholar 

  2. Hart, R.W. and Turturro, A. (1983): Species longevity as an indicator for extrapolation of toxicity data among placental mammals. J. Am. Coll. Toxicol. 2: 235–243.

    Google Scholar 

  3. Ashby, W.R. (1960). “Design for a Brain: The Origin of Adaptive Behavior,” 2 nd ed., Chapman and Hall Ltd., London, p. 12.

    Google Scholar 

  4. Toulmin, S. (1953). “The Philosophy of Science: An Introduction”, Hutchinson, London, p. 44.

    Google Scholar 

  5. Toulman, S. (1961). “Foresight and Understanding,” Hutchinson, London, p. 115.

    Google Scholar 

  6. Suppe, F. (1977). The search for philosophic understanding of scientific theories. In “The Structure of Scientific Theories,” 2nd ed., (F. Suppe, ed.), University of Illinois Press, Urbanna, pp. 3–243.

    Google Scholar 

  7. Fethe, H. (1982). Models’ limits suggest reflexivity in nature. Am. J. Physiol.242: R167-R171.

    CAS  PubMed  Google Scholar 

  8. Georgescu-Roegen, N. (1971): “The Entropy Law and the Economic Process,” Harvard University Press, Cambridge.

    Google Scholar 

  9. Boxenbaum, H. (1983): Evolutionary biology, animal behavior, fourth-dimensional space, and the raison d’être of drug metabolism and pharmacokinetics. Drug Metab. Rev.14: 1057–1097.

    Article  CAS  PubMed  Google Scholar 

  10. Miller, J.G. (1978): “Living Systems,” McGraw-Hill, N.Y., pp. 35–36.

    Google Scholar 

  11. Sacher, G.A. (1965): On longevity regarded as an organized behavior: The role of brain structure. In “Contributions to the Psychobiology of Aging,” (R. Kastenbaum, ed.), Springer, N.Y., Chapter 9, pp. 99–110.

    Google Scholar 

  12. Gould, S.J. (1966): Allometry and size in ontogeny and phylogeny. Biol. Rev.41: 587–640.

    Article  CAS  PubMed  Google Scholar 

  13. Boxenbaum, H. (1980): Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: Extrapolation of data to benzodiazepines and phenytoin J. Pharmacokin. Biopharm.8: 165–176.

    Article  CAS  Google Scholar 

  14. Wilkinson, G.R. and Shand, D.G. (1975): A physiological approach to hepatic drug clearance. Clin. Pharmacol. Therap.18: 377–390.

    CAS  Google Scholar 

  15. Pang, K.S. and Rowland, M. (1977): Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance J. Pharmacokin. Biopharm.5: 625–653.

    Article  CAS  Google Scholar 

  16. Rowland, M. (1972). Influence of route of administration on drug availability J. Pharm. Sei.61: 70–74.

    Article  CAS  Google Scholar 

  17. Boxenbaum, H. (1982): Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J. Pharmacokin. Biopharm.10: 201–227.

    Article  CAS  Google Scholar 

  18. Sacher, G.A. and Staffeldt, E.F. (1974): Relation of gestation time to brain weight for placental mammals: Implications for the theory of vertebrate growth. American Naturalist.108: 593–615.

    Article  Google Scholar 

  19. Jerison, H.J. (1973). “Evolution of the Brain and Intelligence,” Academic Press, N.Y., pp. 392–393.

    Google Scholar 

  20. Altman, P.L. and Dittmer, D.S. (1962). “Growth, including Reproduction and Morphological Development,” Federation of American Societies for Experimental Biology, Wash. D.C., p. 357.

    Google Scholar 

  21. Dawson, T.J. (1973): “Primative” mammals. In “Comparative Physiology of Thermoregulation. Special Aspects of Thermoregulation. ” Vol. III, (G.C. Whittow (ed.), Academic Press, N.Y., Chapter 1, pp. 1–46.

    Google Scholar 

  22. Spector, W.S. (ed.). (1956). “Handbook of Biological Data,” W.B. Saunders Co., Phila., p. 343.

    Google Scholar 

  23. Altman, P.L. and Dittmer, D.S. (eds.). (1971). “Respiration and Circulation”, Federation of American Societies for Experimental Biology, Bethesda, p. 225.

    Google Scholar 

  24. Whittow, G.C. (1971). Ungulates. In “Comparative Physiology of Thermoregulation. Mammals,” vol. II, (G.C. Whittow, (ed.), Academic Press, N.Y., Chapter 3, pp. 191–281.

    Google Scholar 

  25. Hart, J.S. (1971). Rodents. In “Comparative Physiology of Thermoregulation. Mammals,” vol. II, (G.C. Whittow, (ed.), Academic Press, N.Y., Chapter 1, pp. 1–149.

    Google Scholar 

  26. Altman, P.L. and Dittmer, D.S. (eds.). (1973): “Biology Data Book”, vol. II, 2nd ed., Federation of American Societies for Experimental Biology, Bethesda, p. 863.

    Google Scholar 

  27. Swan, H. (1974): “Thermoregulation and Bioenergetics: Patterns for Vertebrate Survival,” American Elsevier Pub. Co., N.Y., p. 330.

    Google Scholar 

  28. Ray, A.A. (ed.). (1982): “SAS User’s Guide: Statistics” SAS Intitute Inc., Cary, North Carolina.

    Google Scholar 

  29. Cohen, J. and Cohen, P. (1975): “Applied Multiple Regression Correlation: Analysis for the Behavioral Sciences,” Lawrence Erlbaum Associates, Hillsdale, N.J. pp. 106–107.

    Google Scholar 

  30. Sacher, G.A. (1959): Relationship of lifespan to brain weight and body weight in mammals. In “The Lifespan of Animals,” Ciba Foundation Colloquia on Ageing, vol. 5, (G.E.W. Wolstenholme and M. O’Connor, (eds.), Little Brown and Co., Boston, pp. 115–141.

    Google Scholar 

  31. Sacher, G.A. (1978): Longevity and aging in vertebrate evolution. Bioscience.28: 497–501.

    Article  Google Scholar 

  32. Sacher, G. A. (1978): Evolution of longevity and survival characteristics in mammals. In “Genetics of Ageing”, (E.L. Schneider, ed.), Plenum Press, N.Y., Chapter 6, pp. 151–168.

    Google Scholar 

  33. Williams, G.C. (1957): Pleiotropy, natural selection, and the evolution of senescence. Evolution.11: 398–411.

    Article  Google Scholar 

  34. Sacher, G.A. (1966): Abnutzstheorie. In “Perspectives in Experimental Gerontology,” (N.W. Shock, ed.), Charles C. Thomas, Springfield, Ill., pp. 326–335.

    Google Scholar 

  35. Boxenbaum, H., Murray, W., Markin, R. and Ciraulo, D. (1984): Benzodiazepine pharmacokinetics: Clinical highlights and interspecies scaling. In Pharmacokinetics and Pharmacodynamics of Psychoactive Drugs (G. Barnett and N. Chiang, eds.), Marcel Dekker, Inc., N.Y., In press.

    Google Scholar 

  36. Boxenbaum, H. and Ronfeld, R. (1983): Interspecies pharmacokinetic scaling and the Dedrick plots Am. J. Physiol245: R768-R775.

    CAS  PubMed  Google Scholar 

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Author notes

  1. Harold Boxenbaum

    Present address: Pharmaceutics Seciton, School of Pharmacy, University of Connecticut, Building 5, Veterans Administration Medical Center, 555 Willard Avanue, 06111, Newington, Connecticut, USA

Affiliations

  1. Behavioral Medicine Research Laboratory, Veterans Administration Medical Center, Newington, Connecticut, USA

    Joanne B. Fertig

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  1. Harold Boxenbaum
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  2. Joanne B. Fertig
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Boxenbaum, H., Fertig, J.B. Scaling of antipyrine intrinsic clearance of unbound drug in 15 mammalian species. European Journal of Drug Metabolism and Pharmacokinetics 9, 177–183 (1984). https://doi.org/10.1007/BF03189622

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  • DOI: https://doi.org/10.1007/BF03189622

Key words

  • Antipyrine
  • interspecies scaling