Pharmacokinetics of OpdA, an organophosphorus hydrolase, in the African green monkey

Colin J. Jackson, Colin Scott, Angela Carville, Keith Mansfield, David L. Ollis, Steven B. Bird*

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 1.2. mg/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 24. h after each OpdA dose increased 5-fold for the 0.45. mg/kg dose and 11-fold for the 1.2. mg/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.

Original languageEnglish
Pages (from-to)1075-1079
Number of pages5
JournalBiochemical Pharmacology
Volume80
Issue number7
DOIs
Publication statusPublished - Oct 2010
Externally publishedYes

Keywords

  • organophosphorus
  • pesticide
  • hydrolysis
  • monkey

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