Pharmacokinetics and toxicodynamics of pralidoxime effects on paraoxon-induced respiratory toxicity.

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  • Author(s): Houzé P;Houzé P; Mager DE; Risède P; Baud FJ
  • Source:
    Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2010 Aug; Vol. 116 (2), pp. 660-72. Date of Electronic Publication: 2010 May 23.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Oxford University Press Country of Publication: United States NLM ID: 9805461 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0929 (Electronic) Linking ISSN: 10960929 NLM ISO Abbreviation: Toxicol Sci Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Cary, NC : Oxford University Press
      Original Publication: Orlando, FL : Academic Press, c1998-
    • Subject Terms:
      Antidotes/*pharmacology ; Insecticides/*poisoning ; Paraoxon/*poisoning ; Pralidoxime Compounds/*pharmacology ; Respiration/*drug effects; Animals ; Cholinesterases/blood ; Leukocytes/enzymology ; Male ; Models, Biological ; Pralidoxime Compounds/pharmacokinetics ; Rats ; Rats, Sprague-Dawley
    • Abstract:
      Empirical studies suggest that the antidotal effect of pralidoxime depends on plasma concentrations with therapeutic effects associated with concentrations above 4 mg/l. The purpose of this study was to determine the pharmacokinetic-toxicodynamic (PK-TD) relationships for the antidotal effect of pralidoxime on paraoxon-induced toxicity in rats. Diethylparaoxon inactivation of whole-blood cholinesterase activity was studied both in vitro and in male Sprague-Dawley rats. Toxin-induced respiratory effects were measured via whole-body plethysmography in control and pralidoxime-treated animals (50 mg/kg im injection). In the in vitro analysis, cholinesterase reactivation by pralidoxime in blood-poisoned diethylparaoxon (10nM) was proportional to the logarithm of drug concentrations. A mechanism-based TD model was developed, which well described the inhibition of cholinesterases by diethylparaoxon and reactivation with pralidoxime. The in vitro pralidoxime EC(50) was estimated to be 4.67 mg/l. Animals exposed to diethylparaoxon exhibited a decrease in respiratory rate and an increase in expiratory time, and pralidoxime treatment resulted in a rapid complete but transient (< 30 min) correction in respiratory toxicity. In contrast, there was a fast and total reactivation of blood cholinesterase activity over the 210-min study period. The in vitro TD model was extended to capture the time-course of in vivo pralidoxime antidotal effects, which explained the complex relationship between drug exposure and pharmacological response profile. This study provides insights into the role of oxime-rescue of paraoxon-induced toxicity, and the final PK-TD model might prove useful in optimizing the design and development of such therapy.
    • Accession Number:
      0 (Antidotes)
      0 (Insecticides)
      0 (Pralidoxime Compounds)
      EC 3.1.1.8 (Cholinesterases)
      P7MU9UTP52 (pralidoxime)
      Q9CX8P80JW (Paraoxon)
    • Publication Date:
      Date Created: 20100526 Date Completed: 20101028 Latest Revision: 20220317
    • Publication Date:
      20221213
    • Accession Number:
      10.1093/toxsci/kfq152
    • Accession Number:
      20498006