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Drug toxicokinetics: scope and limitations that arise from species differences in pharmacodynamic and carcinogenic responses

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Abstract

Toxicokinetics describes the concentration and time course of a xenobiotic in the circulation under the conditions of a toxicology study. However, the fundamental challenge to the toxicologist, of extrapolating the findings in animals to a risk assessment in humans, requires knowledge and understanding of both the pharmacokinetics and pharmacodynamic responses in each species. This paper exemplifies situations where measurement of plasma concentrations may provide information useful in the design and interpretation of the toxicity observed in a given species; it also illustrates how intrinsic interspecies differences in pharmacodynamic response limit the extrapolation of toxicity data across species. The special case of the multistage cumulative phenomenon of carcinogenicity, with the implications of daily dose, duration of dosing, and species differences in response, is also discussed.

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References

  1. D. A. Smith, M. J. Humphrey, and C. Charuel. Design of toxicokinetic studies.Xenobiotica 20:1187–1199 (1990).

    Article  CAS  PubMed  Google Scholar 

  2. W. E. Lindup. Plasma protein binding of drugs-some basic and clinical aspects.Prog. Drug. Metab. 10:142–185 (1987).

    Google Scholar 

  3. J. M. H. Kremer, J. Wilting, and L. H. M. Janssen. Drug binding to human α-1-acid glycoprotein in health and disease.Pharmacol. Rev. 40:1–42 (1988).

    CAS  PubMed  Google Scholar 

  4. C. Poüs, J.-P. Giraud, C. Damais, D. Raichvarg, and L. Chauvelot-Maachon. Effect of recombinant human interleukin-1β and tumour necrosis factor-α on liver cytochrome P-450 and serum α-1-acid glycoprotein concentrations in the rat.Drug Metab. Dispos.18:467–470 (1990).

    PubMed  Google Scholar 

  5. J. P. Tillement, F. Lhoste, and J. F. Gindicelli. Diseases and drug protein binding.Clin. Pharmacokin. 3:144–154 (1978).

    Article  CAS  Google Scholar 

  6. N. Tumer, P. J. Scarpace, and D. T. Lowenthal. Geriatric Pharmacology: basic and clinical considerations.Ann. Rev. Pharmacol. Toxicol. 32:271–302 (1992).

    Article  CAS  Google Scholar 

  7. L. S. Birnbaum. Pharmacokinetic basis of age-related changes in sensitivity to toxicants.Ann. Rev. Pharmacol. 31:101–128 (1991).

    Article  CAS  Google Scholar 

  8. J. K. Haseman and S. K. Seilkop. An examination of the association between maximum tolerated dose and carcinogenicity in 326 long-term studies in rats and mice.Fund. Appl. Toxicol. 19:207–213 (1992).

    Article  CAS  Google Scholar 

  9. A. Monro. What is an appropriate measure of exposure when testing drugs for carcinogenicity in rodents?Toxicol. Appl. Pharmacol. 112:171–181 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. P. A. J. Speth, P. C. M. Linssen, J. B. M. Boeseman, H. M. C. Wessels, and C. Haanen. Cellular and plasma adriamycin concentrations in long-term infusion therapy of leukemia patients.Cancer Chemother. Pharmacol. 20:305–310 (1987).

    CAS  PubMed  Google Scholar 

  11. R. M. Shepard and F. C. Falkner. Pharmacokinetics of azithromycin in rats and dogs.J. Antimicrob. Chemother. 25 (Suppl. A); 49–60 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. D. W. Nebert, D. R. Nelson, M. J. Coon, R. W. Estabrook, R. Feyereisen, Y. Fujii-Kuriyama, F. P. Gonzalez, F. P. Guengerich, I. C. Gunsalus, E. F. Johnson, J. C. Loper, R. Sato, M. R. Waterson, and D. J. Waxman. The P-450 superfamily: update on new sequences, gene mapping, and recommended nomenclature.DNA Cell Biol. 10:1–14 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. M. J. Coon, X. Ding, S. J. Pernecky, and A. D. N. Vaz. Cytochrome P-450: progress and prediction.Fed. Am. Soc. Exp. Biol. J. 6:669–673; and 12 other papers on the same subject, pp. 674–748 (1992).

    CAS  Google Scholar 

  14. M. J. Humphrey and D. A. Smith. Role of metabolism and pharmacokinetic studies in the discovery of new drugs-present and future perspectives.Xenobiotica 22:743–755 (1992).

    Article  CAS  PubMed  Google Scholar 

  15. A. Mukherjee, Z. Haghani, J. Brady, L. Bush, W. McBride, L. M. Buja, and J. T. Willerson. Differences in myocardial α- and β-adrenergic receptor numbers in different species.Am. J. Physiol. 245:H957–61 (1983).

    CAS  PubMed  Google Scholar 

  16. J. M. Palacios, D. Hoyer, and R. Cortés. α1-Adrenoreceptors in the mammalian brain: similar pharmacology but different distribution in rodent and primates.Brain Res. 419:65–75 (1987).

    Article  CAS  PubMed  Google Scholar 

  17. D. Langin, M. P. Portillo, J.-S. Saulnier-Blache, and M. Lafontan. Co-existence of three β-adrenoreceptor subtypes in white fat cells of various mammalian species.Eur. J. Pharmacol. 199:291–301 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. D. Hoyer, A. Pazos, A. Probst, and J. M. Palacios. Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HTIA recognition sites. Apparent absence of 5-HTIB recognition sites.Brain Res. 376:85–96 (1986).

    Article  CAS  PubMed  Google Scholar 

  19. H.-T. Kao, N. Adham, M. A. Olsen, R. L. Weinshank, T. A. Branchek, and P. R. Hartig. Site-directed mutagenesis of a single residue changes the binding properties of the serotonin 5-HT2 receptor from a human to a rat pharmacology.Fed. Eur. Biochem. Soc. 307:324–328 (1992).

    Article  CAS  Google Scholar 

  20. G. J. Kilpatrick and M. B. Tyers. Inter-species variants of the 5-HT3 receptor.Biochem. Soc. Trans. 20:118–121 (1992).

    CAS  PubMed  Google Scholar 

  21. H. Vainio, M. Coleman, and J. Wilbourn. Carcinogenicity evaluation and ongoing studies: the IARC databases.Environ Health Perspect. 96:5–9 (1991).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. L. S. Gold, L. Bernstein, R. Magaw, and T. Stone. Interspecies extrapolation in carcinogenesis: Prediction between rats and mice.Environ. Health Perspect. 81:211–219 (1989).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. J. Huff, J. Haseman, and D. Rall. Scientific concepts, value, and significance of chemical carcinogenesis studies.Ann. Rev. Pharmacol. Toxicol. 31:621–652 (1991).

    Article  CAS  Google Scholar 

  24. B. N. Ames and L. W. Gold. Too many rodent carcinogens: Mitogenesis increases carcinogenesis.Science 249:970–971 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. A. Monro. How useful are chronic (life-span) toxicology studies in rodents in identifying pharmaceuticals which pose a carcinogenic risk to humans?Adverse Drug Reactions Toxicol. Rev. 12:5–34 (1993).

    CAS  Google Scholar 

  26. G. Goodman and R. Wilson. Quantitative prediction of human cancer risk from rodent carcinogenic potencies: a close look at the epidemiological evidence for some chemicals not definitively carcinogenic in humans.Reg. Toxicol. Pharmacol. 14:118–146 (1991).

    Article  CAS  Google Scholar 

  27. N. J. Wald and R. Doll (eds.)Interpretation of Negative Epidemiological Evidence for Carcinogenicity. International Agency for Research on Cancer. Lyon, 1985 (Sci. Publ. No. 65).

    Google Scholar 

  28. A. M. Monro. The paradoxical lack of interspecies correlations between plasma concentrations and chemical carcinogenicity.Reg. Toxicol. Pharmacol. 18:115–135 (1993).

    Article  CAS  Google Scholar 

  29. S. H. Moolgavkar and A. G. Knudson. Mutation and Cancer: A model for human carcinogenesis.J. Natl. Cancer Inst. 66:1037–1052 (1981).

    CAS  PubMed  Google Scholar 

  30. R. B. Connolly, R. H. Reitz, H. J. Clewell, and M. E. Andersen. Pharmacokinetics, biochemical mechanism, and mutation accumulation: A comprehensive model of chemical carcinogenesis.Toxicol. Lett. 43:189–200 (1988).

    Article  Google Scholar 

  31. S. M. Cohen and L. B. Ellwein. Genetic errors, cell proliferation, and carcinogenesis.Cancer Res. 51:6493–6505 (1991).

    CAS  PubMed  Google Scholar 

  32. B. E. Butterworth, T. J. Slaga, W. Farland, and R. M. McLain (eds.)Chemically Induced Cell Proliferation, Wiley-Liss, New York, 1991.

    Google Scholar 

  33. M. L. Cunningham, J. Foley, R. R. Maronpot, and H. B. Matthews, Correlation of hepatocellular proliferation with hepatocarcinogenicity induced by the mutagenic noncarcinogen: carcinogen pair-2,6-and 2,4-diaminotoluene.Toxicol. Appl. Pharmacol. 107:562–567 (1991).

    Article  CAS  PubMed  Google Scholar 

  34. H. Druckrey and K. Küpfmüller. Quantitative Analyse der Krebsentstehung.Z. Naturforsch 96:254–266 (1948).

    Google Scholar 

  35. R. Peto, F. J. C. Roe, P. N. Lee, L. Levy, and J. Clark. Cancer and aging in mice and men.Br. J. Cancer 32:411–426 (1975).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. A. M. Shipp, K. S. Crump, and B. C. Allen. Correlation between carcinogenic potency of chemicals in animals and man.Comm. Toxicol. 2:289–303 (1988).

    CAS  Google Scholar 

  37. G. Goodman and R. Wilson. Predicting the carcinogenicity of chemicals in humans from rodent bioassay data.Environ. Health Perspect. 94:195–218 (1991).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. R. E. Shore, V. Iyer, B. Altshuler, and B. S. Pasternack. Use of human data in quantitative risk assessment of carcinogens: impact an epidemiologic practice and the regulatory process.Reg. Toxicol. Pharmacol. 15:180–221 (1992).

    Article  CAS  Google Scholar 

  39. B. N. Ames and L. W. Gold. Chemical carcinogenesis: Too many carcinogens.Proc. Natl. Acad. Sci. 87:7772–7776 (1990).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Pfizer Central Research, 06340, Groton, Connecticut

    Alastair Monro

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  1. Alastair Monro
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Presented in part at a DIA Workshop: Toxicokinetics: The Way Forward, Nice, France, February 24–26, 1993.

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Monro, A. Drug toxicokinetics: scope and limitations that arise from species differences in pharmacodynamic and carcinogenic responses. Journal of Pharmacokinetics and Biopharmaceutics 22, 41–57 (1994). https://doi.org/10.1007/BF02353409

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  • DOI: https://doi.org/10.1007/BF02353409

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