title: Pharmacokinetics and toxicodynamics of pralidoxime effects on paraoxon-induced respiratory toxicity.
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.
authors.affiliation: Biochemistry Laboratory, AP-HP, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, 75010 Paris, France. pascal.houze@sls.aphp.fr
authors.forename: Pascal
authors.initials: P
authors.lastname: Houzé
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
authors.forename: Patricia
authors.initials: P
authors.lastname: Risède
authors.forename: Frédéric J
authors.initials: FJ
authors.lastname: Baud
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D002802:Cholinesterases / Q000097:blood; D007306:Insecticides / Q000506:poisoning*; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D008954:Models, Biological; D010261:Paraoxon / Q000506:poisoning*; D011220:Pralidoxime Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects*
chemical_list: D000931:Antidotes; D007306:Insecticides; D011220:Pralidoxime Compounds; D002802:Cholinesterases; C028797:pralidoxime; D010261:Paraoxon