Introduction to Pharmacokinetics in Clinical Toxicology

  • Pavan Vajjah
  • Geoffrey K. Isbister
  • Stephen B. Duffull
Protocol
First Online:
Part of the Methods in Molecular Biology book series (MIMB, volume 929)

Abstract

In clinical toxicology, a better understanding of the pharmacokinetics of the drugs may be useful in both risk assessment and formulating treatment guidelines for patients. Pharmacokinetics describes the time course of drug concentrations and is a driver for the time course of drug effects. In this chapter pharmacokinetics is described from a mathematical modeling perspective as applied to clinical toxicology. The pharmacokinetics of drugs are described using a combination of input and disposition (distribution and elimination) phases. A description of the time course of the input and disposition of drugs in overdose provides a basis for understanding the time course of effects of drugs in overdose. Relevant clinical toxicology examples are provided to explain various pharmacokinetic principles. Throughout this chapter we have taken a pragmatic approach to understanding and interpreting the time course of drug effects.

Key words

Pharmacokinetics Clinical toxicology Input Disposition Clearance Volume of distribution Compartmental models 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Dawson AH, Whyte IM (2001) Therapeutic drug monitoring in drug overdose. Br J Clin Pharmacol 52(Suppl 1):97S–102SPubMedCrossRefGoogle Scholar
  2. 2.
    Isbister GK (2010) How do we use drug concentration data to improve the treatment of overdose patients? Ther Drug Monit 32:300–304PubMedCrossRefGoogle Scholar
  3. 3.
    Isbister GK, Friberg LE, Duffull SB (2006) Application of pharmacokinetic-pharmacodynamic modelling in management of QT abnormalities after citalopram overdose. Intensive Care Med 32:1060–1065PubMedCrossRefGoogle Scholar
  4. 4.
    Friberg LE, Isbister GK, Duffull SB (2006) Pharmacokinetic-pharmacodynamic modelling of QT interval prolongation following citalopram overdoses. Br J Clin Pharmacol 61:177–190PubMedCrossRefGoogle Scholar
  5. 5.
    Martinez MN, Amidon GL (2002) A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 42:620–643PubMedCrossRefGoogle Scholar
  6. 6.
    Lin JH, Chiba M, Baillie TA (1999) Is the role of the small intestine in first-pass metabolism overemphasized? Pharmacol Rev 51:135–158PubMedGoogle Scholar
  7. 7.
    Hoppu K, Koskimies O, Holmberg C, Hirvisalo EL (1991) Evidence for pre-hepatic metabolism of oral cyclosporine in children. Br J Clin Pharmacol 32:477–481PubMedCrossRefGoogle Scholar
  8. 8.
    Pacifici GM, Eligi M, Giuliani L (1993) (+) and (−) terbutaline are sulphated at a higher rate in human intestine than in liver. Eur J Clin Pharmacol 45:483–487PubMedCrossRefGoogle Scholar
  9. 9.
    Tanigawara Y, Okamura N, Hirai M, Yasuhara M, Ueda K, Kioka N, Komano T, Hori R (1992) Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). J Pharmacol Exp Ther 263:840–845PubMedGoogle Scholar
  10. 10.
    Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB (1999) OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 27:866–871PubMedGoogle Scholar
  11. 11.
    Lindenberg M, Kopp S, Dressman JB (2004) Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm 58:265–278PubMedCrossRefGoogle Scholar
  12. 12.
    Friberg LE, Isbister GK, Hackett LP, Duffull SB (2005) The population pharmacokinetics of citalopram after deliberate self-poisoning: a Bayesian approach. J Pharmacokinet Pharmacodyn 32:571–605PubMedCrossRefGoogle Scholar
  13. 13.
    Isbister GK, Friberg LE, Hackett LP, Duffull SB (2007) Pharmacokinetics of quetiapine in overdose and the effect of activated charcoal. Clin Pharmacol Ther 81:821–827PubMedCrossRefGoogle Scholar
  14. 14.
    Kumar VV, Oscarsson S, Friberg LE, Isbister GK, Hackett LP, Duffull SB (2009) The effect of decontamination procedures on the pharmacokinetics of venlafaxine in overdose. Clin Pharmacol Ther 86:403–410PubMedCrossRefGoogle Scholar
  15. 15.
    Buckley NA, Dawson AH, Reith DA (1995) Controlled release drugs in overdose: clinical considerations. Drug Saf 12:73–84PubMedCrossRefGoogle Scholar
  16. 16.
    Brahmi N, Kouraichi N, Thabet H, Amamou M (2006) Influence of activated charcoal on the pharmacokinetics and the clinical features of carbamazepine poisoning. Am J Emerg Med 24:440–443PubMedCrossRefGoogle Scholar
  17. 17.
    Hulten BA, Heath A, Knudsen K, Nyberg G, Starmark JE, Martensson E (1992) Severe amitriptyline overdose: relationship between toxicokinetics and toxicodynamics. J Toxicol Clin Toxicol 30:171–179PubMedCrossRefGoogle Scholar
  18. 18.
    Hulten BA, Heath A, Knudsen K, Nyberg G, Svensson C, Martensson E (1992) Amitriptyline and amitriptyline metabolites in blood and cerebrospinal fluid following human overdose. J Toxicol Clin Toxicol 30:181–201PubMedCrossRefGoogle Scholar
  19. 19.
    Meineke I, Schmidt W, Nottrott M, Schroder T, Hellige G, Gundert-Remy U (1997) Modelling of non-linear pharmacokinetics in sheep after short-term infusion of cardiotoxic doses of imipramine. Pharmacol Toxicol 80:266–271PubMedCrossRefGoogle Scholar
  20. 20.
    Waring WS (2006) Management of lithium toxicity. Toxicol Rev 25:221–230PubMedCrossRefGoogle Scholar
  21. 21.
    Sproule BA, Hardy BG, Shulman KI (2000) Differential pharmacokinetics of lithium in elderly patients. Drugs Aging 16:165–177PubMedCrossRefGoogle Scholar
  22. 22.
    Balit CR, Daly FFS, Little M, Murray L (2006) Oral methotrexate overdose. Clin Toxicol 44:1Google Scholar
  23. 23.
    Sanford M, Plosker GL (2008) Dabigatran etexilate. Drugs 68:1699–1709PubMedCrossRefGoogle Scholar
  24. 24.
    Goldblum R (1993) Therapy of rheumatoid arthritis with mycophenolate mofetil. Clin Exp Rheumatol 11(Suppl 8):S117–S119PubMedGoogle Scholar
  25. 25.
    Watson CP, Vernich L, Chipman M, Reed K (1998) Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology 51:1166–1171PubMedCrossRefGoogle Scholar
  26. 26.
    Tashkin DP, Brik A, Gong H Jr (1987) Cetirizine inhibition of histamine-induced bronchospasm. Ann Allergy 59:49–52PubMedGoogle Scholar
  27. 27.
    Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT (2000) Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 67:275–282PubMedCrossRefGoogle Scholar
  28. 28.
    Schmidt LE, Dalhoff K, Poulsen HE (2002) Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Hepatology 35:876–882PubMedCrossRefGoogle Scholar
  29. 29.
    Thummel KE, Slattery JT, Ro H, Chien JY, Nelson SD, Lown KE, Watkins PB (2000) Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults. Clin Pharmacol Ther 67:591–599PubMedCrossRefGoogle Scholar
  30. 30.
    Levy G, Galinsky RE, Lin JH (1982) Pharmacokinetic consequences and toxicologic implications of endogenous cosubstrate depletion. Drug Metab Rev 13:1009–1020PubMedCrossRefGoogle Scholar
  31. 31.
    Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT (2007) Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults. Clin Pharmacol Ther 81:840–848PubMedCrossRefGoogle Scholar
  32. 32.
    Tirona RG, Kim RB (2002) Pharmacogenomics of organic anion-transporting polypeptides (OATP). Adv Drug Deliv Rev 54:1343–1352PubMedCrossRefGoogle Scholar
  33. 33.
    Levy G, Tsuchiya T (1972) Salicylate accumulation kinetics in man. N Engl J Med 287:430–432PubMedCrossRefGoogle Scholar
  34. 34.
    Done AK (1960) Salicylate intoxication. Significance of measurements of salicylate in blood in cases of acute ingestion. Pediatrics 26:800–807PubMedGoogle Scholar
  35. 35.
    Cumming G, Dukes DC, Widdowson G (1964) Alkaline diuresis in treatment of aspirin poisoning. Br Med J 2:1033–1036PubMedCrossRefGoogle Scholar
  36. 36.
    Rosenzweig P, Canal M, Patat A, Bergougnan L, Zieleniuk I, Bianchetti G (2002) A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers. Hum Psychopharmacol 17:1–13PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Pavan Vajjah
    • 1
    • 2
  • Geoffrey K. Isbister
    • 3
    • 4
  • Stephen B. Duffull
    • 1
  1. 1.School of PharmacyUniversity of OtagoOtagoNew Zealand
  2. 2.Systems Pharmacology GroupSimcyp LtdSheffieldUK
  3. 3.Department of Clinical Toxicology and Pharmacology Calvary Mater NewcastleUniversity of NewcastleNewcastleAustralia
  4. 4.Discipline of Clinical PharmacologyUniversity of NewcastleNewcastleAustralia

Personalised recommendations