Pharmacokinetics and pharmacodynamics of obidoxime in sarin-poisoned rats.
The pharmacokinetics and pharmacodynamics of the oxime obidoxime (Toxogonin, 50 mg/kg iv) were investigated in anesthetized normal rats and in sarin-poisoned (50 micrograms/kg iv) rats. The kinetics were described by a two-compartment open model. The elimination half-life ranged from 35 min in normal rats to 86 min in sarin-poisoned rats. Obidoxime excretion occurred predominantly by the renal route, amounting to 4.6% of the administered dose in normal rats and to 0.9% in sarin-poisoned rats within the first hour of administration. The significantly diminished glomerular filtration rate confirmed the retardation of obidoxime excretion in sarin poisoning. The mean arterial blood pressure (MAP) response to obidoxime, measured in normal rats, was a transient hypotension, but to sarin an immediate hypertension. In sarin-poisoned rats the therapeutic sequence of administration of obidoxime and atropine (5 mg/kg iv) seemed to be important: the administration of atropine 10 min after and of obidoxime 20 min after sarin poisoning exerted a stabilizing effect on MAP. No serum albumin binding was found for obidoxime. Competition experiments at the isolated nicotinic receptor demonstrated the anticholinergic activity of obidoxime. The affinity of obidoxime was 1000 times smaller than that of acetylcholine. It is concluded that obidoxime, due to its prolonged residence time in the organism in sarin poisoning, exerts a "curare-like" inhibition and protection of the nicotinic acetylcholine receptor and, combined with atropine, a synergistic effect on blood pressure normalization.
Alioth-Streichenberg
C M
CM
Department of Pharmacology, University of Zurich, Switzerland.
Bodmer
D M
DM
Waser
P G
PG
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D009768:Obidoxime Chloride / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011950:Receptors, Cholinergic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D012524:Sarin / Q000506:poisoning*
D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; D009768:Obidoxime Chloride; D001285:Atropine; D012524:Sarin; D000109:Acetylcholine