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Title: The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound’s PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t1/2 of ~1 hr. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrationsmore » tested. The Cmax in the brain ranged between 0.03-0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.« less
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [1] ;  [1] ; ORCiD logo [1] ;  [1] ;  [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Veterans Affairs, Palo Alto, CA (United States)
Publication Date:
Report Number(s):
LLNL-JRNL-738714
Journal ID: ISSN 0009-2797; 891966
Grant/Contract Number:
AC52-07NA27344
Type:
Accepted Manuscript
Journal Name:
Chemico-Biological Interactions
Additional Journal Information:
Journal Volume: 277; Journal Issue: C; Journal ID: ISSN 0009-2797
Publisher:
Elsevier
Research Org:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org:
USDOE National Nuclear Security Administration (NNSA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES
OSTI Identifier:
1458634

Malfatti, Michael A., Enright, Heather A., Be, Nicholas A., Kuhn, Edward A., Hok, Saphon, McNerney, M. Windy, Lao, Victoria, Nguyen, Tuan H., Lightstone, Felice C., Carpenter, Timothy S., Bennion, Brian J., and Valdez, Carlos A.. The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs. United States: N. p., Web. doi:10.1016/j.cbi.2017.09.016.
Malfatti, Michael A., Enright, Heather A., Be, Nicholas A., Kuhn, Edward A., Hok, Saphon, McNerney, M. Windy, Lao, Victoria, Nguyen, Tuan H., Lightstone, Felice C., Carpenter, Timothy S., Bennion, Brian J., & Valdez, Carlos A.. The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs. United States. doi:10.1016/j.cbi.2017.09.016.
Malfatti, Michael A., Enright, Heather A., Be, Nicholas A., Kuhn, Edward A., Hok, Saphon, McNerney, M. Windy, Lao, Victoria, Nguyen, Tuan H., Lightstone, Felice C., Carpenter, Timothy S., Bennion, Brian J., and Valdez, Carlos A.. 2017. "The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs". United States. doi:10.1016/j.cbi.2017.09.016. https://www.osti.gov/servlets/purl/1458634.
@article{osti_1458634,
title = {The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs},
author = {Malfatti, Michael A. and Enright, Heather A. and Be, Nicholas A. and Kuhn, Edward A. and Hok, Saphon and McNerney, M. Windy and Lao, Victoria and Nguyen, Tuan H. and Lightstone, Felice C. and Carpenter, Timothy S. and Bennion, Brian J. and Valdez, Carlos A.},
abstractNote = {Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound’s PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t1/2 of ~1 hr. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The Cmax in the brain ranged between 0.03-0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.},
doi = {10.1016/j.cbi.2017.09.016},
journal = {Chemico-Biological Interactions},
number = C,
volume = 277,
place = {United States},
year = {2017},
month = {9}
}