Does modulation of organic cation transporters improve pralidoxime activity in an animal model of organophosphate poisoning?
OBJECTIVE
Pralidoxime is an organic cation used as an antidote in addition to atropine to treat organophosphate poisoning. Pralidoxime is rapidly eliminated by the renal route and thus has limited action. The objectives of this work were as follows. 1) Study the role of organic cation transporters in the renal secretion of pralidoxime using organic cation transporter substrates (tetraethylammonium) and knockout mice (Oct1/2⁻/⁻; Oct3⁻/⁻). 2) Assess whether sustained high plasma concentrations increase pralidoxime antidotal activity toward paraoxon-induced respiratory toxicity.


METHODS
INSERM U705, Faculté de Pharmacie, Université Paris Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France.


METHODS
Rodents: Knockout mice (Oct1/2⁻/⁻; Oct3⁻/⁻) and Sprague-Dawley rats.


METHODS
None.


RESULTS
In rats, the renal clearance of pralidoxime was 3.6-fold higher than the creatinine clearance. Pretreatment with tetraethylammonium (75 mg/kg) in rats or deficiencies in organic cation transporters 1 and 2 in mice (Oct1/2⁻/⁻) resulted in a significant increase in plasma pralidoxime concentrations. Lack of Oct3 did not alter plasma pralidoxime concentrations. The antidotal activity of pralidoxime (50 mg/kg intramuscularly) was longer and with greater effect, resulting in a return to normal values when administered to rats pretreated with tetraethylammonium.


CONCLUSIONS
Pralidoxime is secreted in rats and mice by renal Oct1 and/or Oct2 but not by Oct3. Modulation of organic cation transporter activity increased the plasma pralidoxime concentrations and the antidotal effect of pralidoxime with sustained return within the normal range of respiratory variables in paraoxon-poisoned rats. These results suggest a promising approach in an animal model toward the increase in efficiency of pralidoxime. However, further studies are needed before these results are extended to human poisoning.
Neuropsychopharmacologie des addictions, Faculty of Pharmacy, University Paris Descartes, CNRS, UMR8206, and University Denis Diderot, Paris, France. maya.kayouka@gmail.com
Maya
M
Kayouka
Pascal
P
Houzé
Frederic J
FJ
Baud
Salvatore
S
Cisternino
Marcel
M
Debray
Patricia
P
Risède
Alfred H
AH
Schinkel
Jean-Michel
JM
Warnet
D026923:Amino Acid Transport Systems, Basic / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000931:Antidotes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007306:Insecticides / Q000506:poisoning; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D009946:Organothiophosphorus Compounds / Q000506:poisoning*; D010261:Paraoxon / Q000506:poisoning; D010993:Plethysmography, Whole Body; D011220:Pralidoxime Compounds / Q000819:agonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D026923:Amino Acid Transport Systems, Basic; D000931:Antidotes; D007306:Insecticides; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D009946:Organothiophosphorus Compounds; D011220:Pralidoxime Compounds; D000644:Quaternary Ammonium Compounds; C491012:Slc22a2 protein, mouse; C027917:tetramethylammonium; C028797:pralidoxime; D010261:Paraoxon