Drug Metabolism in Normal and Disease States

  • A. H. Conney
  • B. Craver
  • R. Kuntzman
  • E. J. Pantuck


The concept that most patients have the same response to the usual therapeutic dose of a given drug is a plausible but dangerous myth. People differ in their responsiveness to drugs because of differences in receptor sensitivities, because of differences in the absorption and transport of drugs to their receptors, and because of individual differences in rates and pathways of drug metabolism. Table I shows that marked interindividual variations in steady-state blood levels and half-lives occur in different individuals receiving the same dose of a drug. In a recent study, bishydroxy-coumarin, antipyrine, and phenylbutazone were administered successively to seven sets of identical twins and seven sets of fraternal twins (Vesell and Passananti, 1971; Vesell et al., 1971); the range of plasma half-lives was tenfold for bishydroxycoumarin, threefold for antipyrine, and sixfold for phenylbutazone. These marked variations were attributed to genetic factors, since they were greater in the fraternal twins than in the identical twins. Similar results have been obtained in twins during studies with nortriptyline (Alexanderson et al., 1969).


Drug Metabolism Fraternal Twin Uremic Patient Slow Acetylators Hepatic Drug Metabolism 
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  1. Aagaard, G. N., 1972, Postgrad. Med. 52: 115.PubMedGoogle Scholar
  2. Alexanderson, B., Evans, D. A. P., and Sjöqvist, F., 1969, Brit. Med. J. 4: 764.PubMedCrossRefGoogle Scholar
  3. Arnold, K., and Gerber, N., 1970, Clin. Pharmacol. Therap. 11: 121.Google Scholar
  4. Avenia, R. W., 1972, Federation Proc. 31: 547.Google Scholar
  5. Beckett, A. H., and Triggs, E. J., 1967, Nature 216: 587.PubMedCrossRefGoogle Scholar
  6. Bloom, P. M., and Nelp, W. B., 1966, Am. J. Med. Sci. 251: 133.PubMedCrossRefGoogle Scholar
  7. Brain, M. C., and Booth, C. C., 1964, Gut 5: 241.PubMedCrossRefGoogle Scholar
  8. Brodie, B. B., Weiner, M., Burns, J. J., Simson, G., and Yale, E. K., 1952, J. Pharmacol. Exp. Therap. 106: 453.Google Scholar
  9. Brown, R. R., Miller, J. A., and Miller, E. C., 1954, J. Biol. Chem. 209: 211.PubMedGoogle Scholar
  10. Christensen, L. K., and Skövsted, L., 1969, Lancet 2: 1397.PubMedCrossRefGoogle Scholar
  11. Conney, A. H., and Burns, J. J., 1972, Science 178: 576.PubMedCrossRefGoogle Scholar
  12. Conney, A. H., Bray, G. A., Evans, C., and Burns, J. J., 1961, Ann. N.Y. Acad. Sci. 92: 115.PubMedCrossRefGoogle Scholar
  13. Cookesley, W. G. E., and Powell, L. W., 1971, Drugs 2: 177.CrossRefGoogle Scholar
  14. Cucinell, S. A., Conney, A. H., Sansur, M., and Burns, J. J., 1965, Clin. Pharmacol. Therap. 6: 420.Google Scholar
  15. Curry, S. H., and Marshall, J. H. L., 1968, Life Sci. 7: 9.PubMedCrossRefGoogle Scholar
  16. Degkwitz, E., and Staudinger, Hj., 1965, Hoppe-Selyer’s Z. Physiol. Chem. 342: 63.CrossRefGoogle Scholar
  17. Degkwitz, E., Luft, D., Pfeiffer, U., and Staudinger, Hj., 1968, Hoppe-Selyer’s Z. Physiol. Chem. 349: 465.CrossRefGoogle Scholar
  18. Dixon, R. L., Shultice, R. W., and Fouts, J. R., 1960, Proc. Soc. Exp. Therap. 103: 333.Google Scholar
  19. Dollery, C. T., Emslie-Smith, D., and McMichael, J., 1960, Lancet 1: 296.PubMedCrossRefGoogle Scholar
  20. Englert, E., Jr., Brown, H., Willardson, D. G., Wallach, S., and Simons, E.L., 1958, J. Clin. Endocrinol. 18: 36.CrossRefGoogle Scholar
  21. Evans, D. A. P., 1971, Acta Pharmacol. Toxicol. 29: (Suppl. 3), 156.Google Scholar
  22. Faigle, J. W., 1972, Acta Pharmacol. Toxicol. 29: (Suppl. 3), 233.Google Scholar
  23. Fouts, J. R., and Adamson, R. H., 1959, Science 129: 897.PubMedCrossRefGoogle Scholar
  24. Gershberg, H., and Kühl, W. J., Jr., 1950, J. Clin. Invest. 29: 1625.PubMedCrossRefGoogle Scholar
  25. Gillette, J. R., 1971, Ann. N.Y. Acad. Sci. 179: 43.PubMedCrossRefGoogle Scholar
  26. Hammer, W., and Sjöqvist, F., 1967, Life Sci. 6: 1895.PubMedCrossRefGoogle Scholar
  27. Hammer, W., Idestrom, C. W., and Sjöqvist, F., 1967, Excerpta Medica, p. 301. Proc. First International Symposium on Antidepressant Drugs, Milan, 1966.Google Scholar
  28. Harries, J. T., and Müller, D. P. R., 1971, Arch. Diseases Childhood 46: 341.CrossRefGoogle Scholar
  29. Jondorf, W. R., Maickel, R. P., and Brodie, B. B., 1958, Biochem. Pharmacol. 1: 352.CrossRefGoogle Scholar
  30. Kalow, W., 1962, Pharmacogenetics: Heredity and the Response to Drugs, W.B. Saunders Company, Philadelphia.Google Scholar
  31. Kato, R., and Takanaka, A., 1968, Japan J. Pharmacol. 18: 389.CrossRefGoogle Scholar
  32. Kato, R., Takanaka, A., and Oshima, T., 1969, Japan J. Pharmacol. 19: 25.CrossRefGoogle Scholar
  33. Keeri-Szanto, M., and Pomeroy, J. R., 1971, Lancet 1: 947.PubMedCrossRefGoogle Scholar
  34. Koch-Weser, J., and Klein, S. W., 1971, J. Am. Med. Assoc. 215: 1454.CrossRefGoogle Scholar
  35. Koch-Weser, J., 1972, N. Engl. J. Med. 287: 227.PubMedCrossRefGoogle Scholar
  36. Kolmodin, B., Azarnoff, D. L., and Sjöqvist, F., 1969, Clin. Pharmacol. Therap. 10: 638.Google Scholar
  37. Kunin, C. M., and Finland, M., 1959, Am. Med. Assoc. Arch. Intern. Med. 104: 1030.CrossRefGoogle Scholar
  38. Lemberger, L., Tamarkin, N. R., Axelrod, J., and Kopin, I. J., 1971, Science 173: 72.PubMedCrossRefGoogle Scholar
  39. Letteri, J. M., Mellk, H., Louis, S., Kutt, H., Durant, P., and Glazko, A., 1971, New Engl. J. Med. 285: 648.PubMedCrossRefGoogle Scholar
  40. Levi, A. J., Sherlock, S., and Walker, D., 1968, Lancet 1: 1275.PubMedCrossRefGoogle Scholar
  41. Macgregor, A. G., 1965, Proc. Roy. Soc. Med. 58: 943.PubMedGoogle Scholar
  42. MacMahon, M. T., and Neale, G., 1970, Clin. Sci. 38: 197.PubMedGoogle Scholar
  43. Mitchell, J. R., Potter, W. Z., Jollon, D., Davis, D. C., Gillette, J. R., and Brodie, B. B., 1972, Federation Proc. 31: 539.Google Scholar
  44. Nelson, E., 1964, Am. J. Med. Sci. 248: 657.PubMedCrossRefGoogle Scholar
  45. Odar-Cederlöf, I., Lunde, P., and Sjöqvist, F., 1970, Lancet 2: 831.PubMedCrossRefGoogle Scholar
  46. O’Malley, K., Crooks, J., Duke, E., and Stevenson, I. H., 1971, Brit. Med. J. 3: 607.PubMedCrossRefGoogle Scholar
  47. Orme, B. M., and Cutler, R. E., 1969, Clin. Pharm. Therap. 10: 543.PubMedGoogle Scholar
  48. Pantuck, E. J., Kuntzman, R., and Conney, A. H., 1972, Science 175: 1248.PubMedCrossRefGoogle Scholar
  49. Pantuck, E. J., Hsaio, K.-C, Kuntzman, R., and Conney, A.H., 1972, unpublished observations.Google Scholar
  50. Poland, A., Smith, D., Kuntzman, R., Jacobson, M., and Conney, A. H., 1970, Clin. Pharmacol. Therap. 11: 724.Google Scholar
  51. Prescott, L. F., Roscoe, P., Wright, N., and Brown, S. S., 1971, Lancet 1: 519.PubMedCrossRefGoogle Scholar
  52. Reidenberg, M. M., 1971, Renal Function and Drug Action, W. B. Saunders Company, Philadelphia.Google Scholar
  53. Reidenberg, M. M., Kostenbauder, H., and Adams, W., 1969, Metabolism 18: 209.PubMedCrossRefGoogle Scholar
  54. Reidenberg, M. M., Odar-Cederlöf, I., vonBahr, C., Borgå, O., and Sjöqvist, F., 1971, New Engl. J. Med. 285: 264.PubMedCrossRefGoogle Scholar
  55. Reidenberg, M. M., James, M., and Dring, L. G., 1972, Clin. Pharmacol. Therap. 13: 279.Google Scholar
  56. Stevenson, I. H., O’Malley, K., Turnbull, M. J., Ballinger, B. R., 1972, J. Pharm. Pharmacol. 24: 577.PubMedCrossRefGoogle Scholar
  57. Thomson, A. D., 1966, Clin. Sci. 31: 167.PubMedGoogle Scholar
  58. Thomson, P. D., Rowland, M., and Melmon, K. L., 1971, Am. Heart J. 82: 417.PubMedCrossRefGoogle Scholar
  59. Ueda, H., Sakaurai, T., Ota, M., Nakajima, A., Kamii, K., and Naezaawa, H., 1963, Diabetes 12: 414.PubMedGoogle Scholar
  60. Vesell, E. S. and Page, J. G., 1968a, J. Clin. Invest. 47: 2657.PubMedCrossRefGoogle Scholar
  61. Vesell, E.,, and Page, J. G., 1968b, Science 161: 72.PubMedCrossRefGoogle Scholar
  62. Vesell, E.,, and Passananti, G. L., 1971, Clin. Chem. 17: 851.Google Scholar
  63. Vesell, E.,, Passananti, G. T., Greene, F. E., and Page, J. G., 1971, Ann. N.Y. Acad. Sci. 179: 752.PubMedCrossRefGoogle Scholar
  64. Wattenberg, L. W., 1971, Cancer 28: 99.PubMedCrossRefGoogle Scholar
  65. Wattenberg, L. W., Page, M. A., and Leong, J. L., 1968, Cancer Res. 28: 934.PubMedGoogle Scholar
  66. Weiner, M., Shapiro, S., Axelrod, J., Cooper, J. R., and Brodie, B. B., 1950, J. Pharmacol. Exp. Therap. 99: 409.Google Scholar
  67. Weiss, C. F., Glazko, A. J., and Weston, J. K., 1960, New Engl. J. Med. 262: 787.PubMedCrossRefGoogle Scholar
  68. Zannoni, V. G., Flynn, E. J., and Lynch, M., 1972, Biochem. Pharm. 21: 1377.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1972

Authors and Affiliations

  • A. H. Conney
    • 1
  • B. Craver
    • 1
  • R. Kuntzman
    • 1
  • E. J. Pantuck
    • 2
  1. 1.Research DivisionHoffman-La Roche, Inc.NutleyUSA
  2. 2.Department of AnesthesiologyColumbia University College of Physicians and Surgeons and Presbyterian HosptialNew YorkUSA

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