Organophosphorus (OP) pesticides are a broad class of
acetylcholinesterase inhibitors that are responsible for tremendous morbidity and mortality worldwide, contributing to an estimated 300,000 deaths annually. Current
pharmacotherapy for acute OP
poisoning includes the use of
atropine, an
oxime, and
benzodiazepines. However, even with such
therapy, the mortality from these agents are as high as 40%. Enzymatic hydrolysis of OPs is an attractive new potential
therapy for acute OP
poisoning. A number of bacterial OP
hydrolases have been isolated. A promising OP
hydrolase is an
enzyme isolated from Agrobacterium radiobacter, named
OpdA.
OpdA has been shown to decrease lethality in rodent models of
parathion and
dichlorvos poisoning. However, pharmacokinetic data have not been obtained. In this study, we examined the pharmacokinetics of
OpdA in an African Green Monkey model. At a dose of 1.2mg/kg the half-life of
OpdA was approximately 40 min, with a mean residence time of 57 min. As expected, the half-life did not change with the dose of
OpdA given: at doses of 0.15 and 0.45 mg/kg, the half-life of
OpdA was 43.1 and 38.9 min, respectively. In animals subjected to 5 daily doses of
OpdA, the residual activity that was measured 24h after each
OpdA dose increased 5-fold for the 0.45 mg/kg dose and 11-fold for the 1.2mg/kg dose.
OpdA exhibits pharmacokinetics favorable for the further development as a
therapy for acute OP
poisoning, particularly for hydrophilic OP pesticides. Future work to increase the half-life of
OpdA may be beneficial.