Physiological Models, Allometry, Neoteny, Space-Time and Pharmacokinetics

  • Harold Boxenbaum
  • Richard D’Souza
Part of the NATO ASI Series book series (NSSA, volume 145)


The first attempt at developing a mathematical model to describe and predict drug distribution and elimination processes dates back only 50 years. Teorell (1937a,b) advanced a simplified scheme of the body by grouping tissues into five compartments (connected through the circulatory system). This pioneering work has served as the forerunner from which all pharmacokinetic models, physiological and compartmental, have been developed.


Partition Coefficient Pharmacokinetic Model Physiological Model Vide Supra Isolate Liver Cell 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andersen, M. E., Clewell III, H. J., Gargas, M. L., Smith, F. A., and Reitz, R. H., 1987, Physiologically based pharmacokinetics and the risk assessment process for methylene chloride, Toxicol. Appl. Pharmacol., 87:185.PubMedCrossRefGoogle Scholar
  2. Barnard, C. J., 1984, Shrews, in: “All the World’s Animals: Marsupials and Insectivores,” D. Macdonald, ed., Torstar Books, N.Y.Google Scholar
  3. Barnes, R. F. V., 1984, Elephants, in: “All the World’s Animals: Hoofed Mammals,” D. Macdonald, ed., Torstar Books, N.Y.Google Scholar
  4. Barnett, L., 1962, “The Universe and Dr. Einstein,” Time Inc., N.Y.Google Scholar
  5. Barthell Jr., E. E., 1971, “Gods and Goddesses of Ancient Greece,” University of Miami Press, Coral Gables.Google Scholar
  6. Benowitz, N., Forsyth, R. P., Melmon, K. L., and Rowland, M., 1974, Lidocaine disposition kinetics in monkey and man. I. Prediction by a perfusion model, Clin. Pharmacol. Ther., 16:87.PubMedGoogle Scholar
  7. Bischoff, K. B., Dedrick, R. L., Zaharko, D. S., and Longstreth, J. A., 1971, Methotrexate pharmacokinetics, J. Pharm, Sci., 60:1128.CrossRefGoogle Scholar
  8. 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.Google Scholar
  9. Boxenbaum, H., 1982, Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics, J. Pharmacokin. Biopharm., 10:201.Google Scholar
  10. Boxenbaum, H., 1984, Interspecies pharmacokinetic scaling and the evolutionary-comparative paradigm, Drug Metab. Rev., 15:1071.PubMedCrossRefGoogle Scholar
  11. Boxenbaum, H., 1986, Time concepts in physics, biology, and pharmacokinetics, J. Pharm. Sci., 75:1053.PubMedCrossRefGoogle Scholar
  12. Boxenbaum, H., and Ronfeld, R., 1983, Interspecies pharmacokinetic scaling and the Dedrick plots, Am. J. Physiol., 245:R768.PubMedGoogle Scholar
  13. Brown, N. O., 1959, “Life Against Death,” Wesleyan University Press, Middletown.Google Scholar
  14. Calder III, W. A., 1984, “Size, Function, and Life History,” Harvard University Press, Cambridge.Google Scholar
  15. Capra, F., 1975, “The Tao of Physics,” Bantam Books, N.Y.Google Scholar
  16. Carson, E. R., Cobelli, C., and Finkelstein, L., 1983, “The Mathematical Modeling of Metabolic and Endocrine Systems,” John Wiley and Sons, N. Y.Google Scholar
  17. Chen, H. G., and Gross, J. F., 1979, Estimation of tissue-to-plasma partition coefficients used in physiological pharmacokinetic models, J. Pharmacokin. Biopharm., 7:117.Google Scholar
  18. Dedrick, R. L., Forrester, D. D., and Ho, D. H. V., 1972, In vitro - in vivo correlation of drug metabolism - Deamination of 1–beta-Darabinofuranosylcytosine, Biochem. Pharmacol., 21:1.Google Scholar
  19. Dossey, L., 1982, “Space, Time and Medicine,” Shambhala Publications, Inc., Boulder.Google Scholar
  20. D’Souza, R. W., Francis, W. R., Bruce, R. D., and Andersen, M. E., 1987, Physiologic pharmacokinetic model for ethylene dichloride and its application in cancer risk assessment, in: “Pharmacokinetics in Risk Assessment”, National Academy Press, Wash., D.C., In press.Google Scholar
  21. Eiduson, B. T., 1962, “Scientists: Their Psychological World,” Basic Books, Inc., N. Y.Google Scholar
  22. Fethe, H., 1982, Models’ limits suggest reflexivity in nature, Am. J. Physiol., 242:R167.PubMedGoogle Scholar
  23. Fisher, J. W., Andersen, M. E., Clewell III, H. J., and Taylor, D., 1987, Modeling lactational transfer of trichloroethylene (TCE) and its metabolite trichloroacetic acid (TCA) in the rat, The Toxicologist, 7:139.Google Scholar
  24. Galilei, G., 1637, “Dialogues Concerning Two New Sciences,” H. Crew and A. DeSalvio, translators, 1914, Macmillan, N.Y.Google Scholar
  25. Gargas, M. L., Clewell III, H. J., and Andersen, M. E., 1986a, A physiologically based simulation approach for determining metabolic constants from gas uptake data, Toxicol. Appl. Pharmacol., 86:341.PubMedCrossRefGoogle Scholar
  26. Gargas, M. L., Clewell, H. J., and Andersen, 1986b, Metabolism of inhaled dihalomethanes in vivo: differentiation of kinetic constants for the two independent pathways. Toxicol. Appl. Pharmacol.,8 2:211.Google Scholar
  27. Goldsmith, D., and Levy, D., 1974, “From the Black Hole to the Infinite Universe,” Holden-Day, Inc., San Francisco.Google Scholar
  28. Gould, S. J., 1977, “Ontogeny and Phylogeny,” The Belknap Press of Harvard University Press, Cambridge.Google Scholar
  29. Green, G., 1981, On seeing the unseen: Imagination in science and religion, Zygon, 16:15.CrossRefGoogle Scholar
  30. Gregory, W. K., 1951, “Evolution Emerging: A Survey of Changing Patterns from Primeval Life to Man,” Vols. I and II, MacMillan Co., N.Y.Google Scholar
  31. Guerber, H. A., 1921, “Myths of Greece and Rome,” American Book Co., N.Y.Google Scholar
  32. Haldane, J. B. S., 1928, On being the right size, reprinted in: “A Treasury of Science,” H. Shapley, S. Rapport and H. Wright, eds., 1943, Harper and Brothers, N. Y.Google Scholar
  33. Hayward, J. W., 1984, “Perceiving Ordinary Magic,” New Science Library, Boulder.Google Scholar
  34. Kaplan, A., 1964, “The Conduct of Inquiry,” Chandler Publishing Co., San Francisco.Google Scholar
  35. Kimpel, B., 1964, “Kant’s Critique of Pure Reason and Prolegomena,” Student Outlines Co., Boston.Google Scholar
  36. King, F. G., Dedrick, R. L., and Farris, F. F., 1986, Physiological pharmacokinetic modeling of cis-dichlorodiammineplatinum (II) (DDP) in several species, J. Pharmacokin. Biopharm., 14:131.Google Scholar
  37. Kline, M., 1980, “Mathematics: The Loss of Certainty,” Oxford Univ. Press, N.Y.Google Scholar
  38. Landes, D. S., 1983, “Revolution in Time,” The Belknap Press of Harvard University Press, Cambridge.Google Scholar
  39. Lin, J. H., Sugiyama, Y., Awazu, S., and Hanano, M., 1982a, In vitro and in vivo evaluation of the tissue-to-blood partition coefficient for physiological pharmacokinetic models, J. Pharmacokin. Biopharm., 10:637.Google Scholar
  40. Lin, J. H., Sugiyama, Y., Awazu, S., and Hanano, M., 1982b, Physiological pharmacokinetics of ethoxybenzamide based on biochemical data obtained in vitro as well as on physiological data, J. Pharmacokin. Biopharm., 10:649.Google Scholar
  41. Luria, S. E., Gould, S. J., and Singer, S., 1981, “A View of Life,” The Benjamin/Cummings Pub. Co., Inc., Menlo Park.Google Scholar
  42. Lutz, R. J., Galbraith, W. M., Dedrick, R. L., Shrager, R., and Mellett, L. B., 1977, A model for the kinetics of distribution of actinomycin-D in the beagle dog, J. Pharmacol. Exp. Ther., 200:469.PubMedGoogle Scholar
  43. McMahon, T. A., and Bonner, J. T., 1983, “On Size and Life,” Scientific American Books, Inc., N.Y.Google Scholar
  44. Miller, J. G., 1978, “Living Systems,” McGraw-Hill Book Co., N.Y.Google Scholar
  45. Morris, R., 1984, “Time’s Arrows,” Simon and Schuster, N.Y.Google Scholar
  46. Naef, A., 1926, Über die Urformen der anthropomorphen und die Stammesgeschichte des menschenschädels, Naturwissenschaften, 14:445.CrossRefGoogle Scholar
  47. Ouspensky, P. D., 1920, “Tertium Organum,” reprinted in 1982, Vintage Books, N.Y.Google Scholar
  48. Poincaré, H., 1929, “The Foundations of Science” (English translation), Science Press, N.Y.Google Scholar
  49. Ramsey, J. C., and Andersen, M. E., 1984, A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans, Toxicol. Appl. Pharmacol., 73:159.PubMedCrossRefGoogle Scholar
  50. Reiser, O. L., 1931, Relativity and reality, Monist, 41:512.Google Scholar
  51. Rowland, M,, 1984, Physiologic pharmacokinetic models: Relevance, experience, and future trends, Drug Metab. Rev., 15:55.PubMedCrossRefGoogle Scholar
  52. Sacher, G. A., 1959, Relation of lifespan to brain weight and body weight in mammals, in: “The Lifespan of Animals,” G. E. W. Wolstenholme and M. O. O’Connor, eds., Little Brown and Co., Boston.Google Scholar
  53. Sato, A., and Nakajima, T., 1979, Partition coefficients of some aromatic hydrocarbons and ketones in water, blood, and oil, Brit. J. Ind. Med., 36:231.Google Scholar
  54. Schickel, R., 1968, “The World of Goya,” Time-Life Books, N.Y.Google Scholar
  55. Schmidt-Nielsen, K., 1975, Scaling in biology: The consequences of size, J. Exp. Zool., 194:287.PubMedCrossRefGoogle Scholar
  56. Stahl, V. R., 1963, The analysis of biological similarity, Advan. Biol. Med. Phys., 9:355.Google Scholar
  57. 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, Urbana.Google Scholar
  58. Tatlock, J. M., 1917, “Greek and Roman Mythology,” D. AppletonCentury Co., N. Y.Google Scholar
  59. Teorell, T., 1937a, Kinetics of distribution of substances administered to the body. I. The extravascular modes of administration, Arch. Intern. Pharmacodyn., 57:205.Google Scholar
  60. Teorell, T., 1937b, Kinetics of distribution of substances administered to the body. II. The intravascular modes of administration, Arch. Int. Pharmacodyn., 57:226.Google Scholar
  61. Trivers, H., 1985, “The Rhythm of Being: A Study of Temporality,” Philosophical Library, N.Y.Google Scholar
  62. Weiss, P. A., 1969, The living system: Determinism stratified, in: “Beyond Reductionism: New Perspectives in the Life Sciences,” A. Koestler and J. R. Smythies, eds., The MacMillan Co., N.Y.Google Scholar
  63. Wells, H. G., Huxley, J. S., and Wells, G. P., 1931, “The Science of Life,” Doubleday, Doran and Company, London.Google Scholar
  64. Whitrow, G. J., 1980, “The Natural Philosophy of Time,” 2nd ed., Clarendon Press, Oxford.Google Scholar
  65. Yates, F. E., and Kugler, P. N., 1986, Similarity principles and intrinsic geometries: Contrasting approaches to interspecies scaling, J. Pharm. Sci., 75:1019.PubMedCrossRefGoogle Scholar
  66. Zukav, G., 1979, “The Dancing Wu Li Masters,” William Morrow and Co., N.Y.Google Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Harold Boxenbaum
    • 1
  • Richard D’Souza
    • 2
  1. 1.Merrell Dow Research InstituteCincinnatiUSA
  2. 2.Miami Valley LaboratoriesProcter & Gamble CompanyCincinnatiUSA

Personalised recommendations