Pharmacokinetic Considerations in the Toxicologic Evaluation of Xenobiotics

  • Roger K. Verbeeck
Conference paper
Part of the NATO ASI Series book series (volume 93)


Toxicokinetics can be defined as the kinetics of absorption, distribution and elimination (i.e. excretion and metabolism) of toxic substances, including therapeutic agents, in animal species used in experimental toxicology. Toxicokinetics is different from pharmacokinetics in that it describes the rates of absorption, distribution and elimination of xenobiotics at relatively high doses often associated with toxic effects. At these high doses the reversible binding of the xenobiotic to plasma and/or tissue proteins may become saturated, as well as the active transport systems and metabolizing enzymes. Consequently, in toxicokinetics one frequently encounters nonlinearity in these rate processes leading to dose-dependent kinetics. This is in contrast to the pharmacokinetic behavior of most drugs following administration of therapeutic doses which usually can be described in terms of linear kinetics. Another important factor which can account or contribute to dose-dependent toxicokinetic behavior of xenobiotics is the potential interaction of the xenobiotic and/or its metabolites with physiological processes such as regional blood flow, urine pH, gastric emptying, etc (Table 1).


Biliary Excretion Tubular Secretion Glucuronide Conjugate Clofibric Acid Total Plasma Concentration 
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  1. Barr WH (1969) Factors involved in the assessment of systemic or biologic availability of drug products. Drug Info Bull 3: 27–45.Google Scholar
  2. Brunelle FM and Verbeeck RK (1993) Glucuronidation of diflunisal by rat liver microsomes. Effect of microsomal β-glucuronidase activity. Biochem Pharmacol 46: 1953–1958.PubMedCrossRefGoogle Scholar
  3. Caldwell J (1980): Conjugation reactions. In “Concepts in Drug Metabolism. Part A”, Jenner P and Testa B (eds), Marcel Dekker Inc. New York, pp. 211–250.Google Scholar
  4. Cassidy MK and Houston JB (1980) In vivo assessment of extrahepatic conjugative metabolism in first pass effects using the model compound phenol. J Pharm Pharmacol 32: 57–59.PubMedCrossRefGoogle Scholar
  5. Chappell WR and Mordenti J (1991) Extrapolation of toxicological and pharmacological data from animals to humans. In “Advances in Drug Research, Volume 20”, Testa B (ed), Academic Press Limited London, pp. 1–116.Google Scholar
  6. Cheng H and Jusko WJ (1993) Pharmacokinetics of reversible metabolic systems. Biopharm Drug Disp 14: 721–766.CrossRefGoogle Scholar
  7. Diliberto JJ, Kedderis LB, Jackson JA and Birnbaum LS (1993) Effects of dose and routes of exposure on the disposition of 2,3,7,8-[3H]-tetrabromodibenzo-p-dioxin ( TBDD) in the rat. Toxicol Appl Pharmacol 120: 315–326.PubMedCrossRefGoogle Scholar
  8. Duggan DE, Hooke KF, Noll RM and Kwan KC (1975): Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem Pharmacol 25: 1749–1754.CrossRefGoogle Scholar
  9. Faed EM and McQueen EG (1979) Plasma half-life of clofibric acid in renal failure. Br J Clin Pharmacol 7: 407–410.PubMedGoogle Scholar
  10. Galinsky RE and Lavy G (1981) Dose- and time-dependent elimination of acetaminophen in rats: pharmacokinetic implications of cosubstrate depletion. J Pharmacol Exptl Ther 219: 14–20.Google Scholar
  11. Gehring PJ and Young JD (1978) Application of pharmacokinetic principles in practice. In: “Proceedings of the First International Congress on Toxicology. Toxicology as a Predictive Science”, Plaa GL and Duncan WAM (eds), Academic Press New York, pp. 119–141.Google Scholar
  12. Gibaldi M and Perrier D (1982) Pharmacokinetics. Second edition, revised and expanded. Marcel Dekker Inc. New York.Google Scholar
  13. Jusko WJ and Gretch M (1976) Plasma and tissue protein binding of drugs in pharmacokinetics. Drug Metab Rev 5: 43–140.CrossRefGoogle Scholar
  14. Kao J and Carver MP (1990): Cutaneous metabolism of xenobiotics. Drug Metab Rev 22: 363–410.PubMedCrossRefGoogle Scholar
  15. Kedderis GL, Dryoff MC and Rickert DE (1984) Hepatic macromolecular covalent binding of the hepatocarcinogen 2,6- dinitrotoluene and its 2,4-isomer in vivo: modulation by the sulfotransferase inhibitors pentachlorophenol and 2,6-dichloro-4-nitrophenol. Carcinogenesis 5: 1199–1204.PubMedCrossRefGoogle Scholar
  16. Klaassen CD and Watkins III JB (1984) Mechanisms of bile formation, hepatic uptake, and biliary excretion. Pharmacol Rev 36: 1–67.PubMedGoogle Scholar
  17. Krishna DR and Klotz U (1994) Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet 26: 144–160.PubMedCrossRefGoogle Scholar
  18. Levy G (1968) Dose dependent effects in pharmacokinetics. In “Importance of Fundamental Principles in Drug Evaluation”, DH Tedeschi and RE Tedeschi (eds.), Raven Press New York, pp. 141–172.Google Scholar
  19. Levy G (1986) Sulfate conjugation in drug metabolism: role of inorganic sulfate. Fed Proc 45: 2235–2240.PubMedGoogle Scholar
  20. Levy G (1993) The case for preclinical pharmacodynamics. In “Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development”, A. Yacobi, JP Skelly, VP Shah and LZ Benet (eds.), Plenum Press New York, pp. 7–13.Google Scholar
  21. Long RM and Rickert DE (1982) Metabolism and excretion 2,6-dinitro-[14C]-toluene in vivo and in isolated perfused rat livers. Drug Metab Disp 10: 455–458.Google Scholar
  22. Masters BSS, Muerhoff AS and Okita RT (1987) Enzymology of extrahepatic cytochromes P-450. In “Mammalian Cytochromes P-450”, FP Guengerich FP (ed), CRC Press, Boca Raton FL, pp. 107–132.Google Scholar
  23. Meffin PJ, Zilm DM and Veenendaal JR (1983) Reduced clofibric acid clearance in renal dysfunction is due to a futile cycle. J Pharmacol Exptl Ther 227: 732–738.Google Scholar
  24. Mirsalis JC and Butterworth BE (1982) Induction of unscheduled DNA synthesis in rat hepatocytes following in vivo treatment with dinitrotoluene. Carcinogenesis 3: 241–245.PubMedCrossRefGoogle Scholar
  25. Mitchell JR, Potter WZ, Hinson JA, Snodgrass WR, Timbrell JA and Gillette JR (1975) Toxic drug reactions. In “:Handbook of Experimental Pharmacology Vol 28 Part 3. Concepts of Biochemical Pharmacology”, JR Gillette and JR Mitchell (eds.), Springer Verlag, Berlin, pp. 383–419.Google Scholar
  26. Mulder GJ (1982) Pharmacological effects of drug conjugates: is morphine-6-glucuronide an exception? Trends Pharmacol Sci 13: 302–304.CrossRefGoogle Scholar
  27. Peck CC (1993) Rationale for the effective use of pharmacokinetics and pharmacodynamics in early drug development. In “Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development”, A. Yacobi, JP Skelly, VP Shah and LZ Benet (eds.), Plenum Press New York, pp. 1–6.Google Scholar
  28. Pond SM and Tozer TN (1984) First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet 9: 1–25.PubMedCrossRefGoogle Scholar
  29. Puigdemont A, Arboix M, Gaspari F, Bortolotti A and Bonati M (1989) In vitro plasma protein binding of propafenone and protein profile in eight mammalian species. Res Comm Chem Pathol Pharmacol 64: 435–440.Google Scholar
  30. Renwick AG (1985): The disposition of saccharin in animals and man - a review. Food Chem. Toxicol. 23: 429–435.Google Scholar
  31. Rowland M and Tozer TN (1989): Clinical Pharmacokinetics. Concepts and Applications. Lea & Febiger Philadelphia.Google Scholar
  32. Sallustio BC, Purdie YJ, Birkett DJ and Meffin PJ (1989) Effect of renal dysfunction on the individual components of the acyl-glucuronide futile cycle. J Pharmacol Exptl Ther 251: 288–294.Google Scholar
  33. Sauerhoff MW, Braun WH, Blau GE and Gehring PJ (1976): The dose-dependent pharmacokinetic profile of 2,4,5-trichlorophenoxy acetic acid following intravenous administration to rats. Toxicol Appl Pharmacol 36: 491–501.PubMedCrossRefGoogle Scholar
  34. Smith PC, McDonagh AF and Benet LZ (1990) Effect of esterase inhibition on the disposition of zomepirac glucuronide and its covalent binding to plasma proteins in the guinea pig. J Pharmacol Exptl Ther 252: 218–224.Google Scholar
  35. Spahn-Langguth H and Benet LZ (1992) Acyl glucuronides revisited: is the glucuronidation process a toxification as well as a detoxification mechanism? Drug Metab Rev 24: 5–48.PubMedCrossRefGoogle Scholar
  36. Sweatman TW and Renwick AG (1980) The tissue distribution and pharmacokinetics of saccharin in the rat. Toxicol Appl Pharmacol 55: 18–31.PubMedCrossRefGoogle Scholar
  37. Timbrell JA (1991) Principles of Biochemical Toxicology, Taylor & Francis London.Google Scholar
  38. Tozer TN (1984) Implications of altered plasma protein binding in disease states. In “Pharmacokinetic Basis for Drug Treatment”, Benet LZ, Massoud N and Gambertoglio JG (eds), Raven Press New York, pp. 173–193.Google Scholar
  39. Varga F (1969) Intestinal absorption of chloroquine in rats. Arch Int Pharmacodyn Therap 163: 38–46.Google Scholar
  40. Walaszek Z (1990) Potential use of D-glucaric acid derivatives in cancer prevention. Cancer Lett 54: 1–8.PubMedCrossRefGoogle Scholar
  41. Walaszek Z, Hanausek-Walaszek M and Webb TE (1984): Inhibition of 7,12-dimethylbenzanthracene-induced rat mammary tumorigenesis by 2,5-di-9-acetyl-D-glucaro-1,4:6,3- dilactone, a β-glucuronidase inhibitor. Carcinogenesis 5: 767–772.PubMedCrossRefGoogle Scholar
  42. Welling PG (1993) Pharmacokinetic principles: linear and nonlinear. In “Drug Toxicokinetics”, Welling PG and de la Iglesia FA (eds), Marcel Dekker Inc. New York, pp. 19–41.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • Roger K. Verbeeck
    • 1
  1. 1.Pharmacokinetics and Drug Metabolism Laboratory, School of PharmacyCatholic University of LouvainBrusselsBelgium

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