Pharmacokinetic study of nerve agent antidotes in blood and target

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S3.9
Pharmacokinetic study of nerve agent antidotes in blood and target tissues
Armstrong S.J.1,2
1. Dstl, Biomedical Sciences, Porton Down, Salisbury, Wiltshire, SP4 0JQ, UK.
2. Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton
General Hospital, MP 887, Southampton, Hampshire, SO16 6YD, UK.
Objectives: Nerve agents irreversibly bind to acetylcholinesterase causing an
overstimulation and subsequent failure of cholinergic signalling. Therapy of atropine
(muscarinic antagonist), Avizafone (diazepam prodrug) and HI-6 (acetylcholinesterase
reactivator) has proven efficacious against nerve agent lethality in animals. Pharmacokinetics
(PK) can be used to optimise regimens for maximal efficacy, but have not been
systematically examined for the triple therapy. Furthermore, the PK of these drugs in target
tissues has not been investigated. Here the PK of the triple therapy were characterised in the
blood, brain and muscle of conscious ambulatory guinea pigs using continuous microdialysis
sampling , with the objective of generating data which can be used to optimise dosing
regimens and aid extrapolation to humans.
Methods: Guinea pigs were surgically prepared with arterial cannulae, brain and muscle
microdialysis probes (20 kDa MWCO, CMA). Atropine, Avizafone and HI-6 were
administered by the intramuscular route. Blood samples were collected using an automated
system. The microdialysis probes were perfused at 2.0 µL/min, dialysate was collected at
regular intervals for four hours post administration. Drug concentration was quantified by
liquid chromatograpy tandem mass spectrometry.
Results: Atropine, Avizafone and HI-6 were rapidly absorbed, distributed and eliminated in
guinea pig plasma. Atropine and HI-6 concentrations in muscle were eliminated at similar
rates to the blood, as was the concentration of HI-6 in the brain. Diazepam was quantified at
lower concentrations in dialysate fractions and appeared to be eliminated more slowly.
Pharmacokinetic profiles of atropine, diazepam and HI-6 quantified in plasma (red line with symbols, n=5), brain microdialysate
(blue line, n=5) and muscle microdialysate (green line, n=6) from conscious guinea pigs following combined intramuscular
administration of atropine sulphate (17.4 mg/kg), Avizafone (3.14 mg/kg) and HI-6 dimethanesulphonate (27.9 mg/kg). Data
shown as mean ± SE.
Conclusion: The PK of triple therapy drugs have been characterised, providing a rationale
for their efficacy against acute nerve agent exposure. These data can be used to model
different regimens to optimise their use against different nerve agent exposure
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