These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Pharmacokinetics and toxicodynamics of pralidoxime effects on paraoxon-induced respiratory toxicity.
    Author: Houzé P, Mager DE, Risède P, Baud FJ.
    Journal: Toxicol Sci; 2010 Aug; 116(2):660-72. PubMed ID: 20498006.
    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.
    [Abstract] [Full Text] [Related] [New Search]