Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

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

Abstract

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]
+ Show Author Affiliations
  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:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1458634
Alternate Identifier(s):
OSTI ID: 1549214
Report Number(s):
LLNL-JRNL-738714
Journal ID: ISSN 0009-2797; 891966
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
Chemico-Biological Interactions
Additional Journal Information:
Journal Volume: 277; Journal Issue: C; Journal ID: ISSN 0009-2797
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

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., 2017. Web. doi:10.1016/j.cbi.2017.09.016.
Copy to clipboard
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. https://doi.org/10.1016/j.cbi.2017.09.016
Copy to clipboard
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. Thu . "The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs". United States. https://doi.org/10.1016/j.cbi.2017.09.016. https://www.osti.gov/servlets/purl/1458634.
Copy to clipboard
@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}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1016/j.cbi.2017.09.016
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 3 works
Citation information provided by
Web of Science
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

Species Difference of Esterase Expression and Hydrolase Activity in Plasma
journal, October 2012

  • Bahar, Fatma Goksin; Ohura, Kayoko; Ogihara, Takuo
  • Journal of Pharmaceutical Sciences, Vol. 101, Issue 10
  • DOI: 10.1002/jps.23258

Evaluation of Microdosing to Assess Pharmacokinetic Linearity in rats Using Liquid Chromatography-Tandem mass Spectrometry
journal, December 2005

  • Balani, Suresh K.; Nagaraja, Nelamangala V.; Qian, Mark G.
  • Drug Metabolism and Disposition, Vol. 34, Issue 3
  • DOI: 10.1124/dmd.105.007195

Predicting a Drug’s Membrane Permeability: A Computational Model Validated With in Vitro Permeability Assay Data
journal, May 2017

  • Bennion, Brian J.; Be, Nicholas A.; McNerney, M. Windy
  • The Journal of Physical Chemistry B, Vol. 121, Issue 20
  • DOI: 10.1021/acs.jpcb.7b02914

Comparison of human and guinea pig acetylcholinesterase sequences and rates of oxime-assisted reactivation
journal, September 2010

  • Cadieux, C. Linn; Broomfield, Clarence A.; Kirkpatrick, Melanie G.
  • Chemico-Biological Interactions, Vol. 187, Issue 1-3
  • DOI: 10.1016/j.cbi.2010.04.020

The permeation of several materials into the fluids of the rabbit's brain
journal, October 1971

Permeability Studies on In Vitro Blood–Brain Barrier Models: Physiology, Pathology, and Pharmacology
journal, February 2005

  • Deli, Mária A.; Ábrahám, Csongor S.; Kataoka, Yasufumi
  • Cellular and Molecular Neurobiology, Vol. 25, Issue 1
  • DOI: 10.1007/s10571-004-1377-8

Pro-2-PAM therapy for central and peripheral cholinesterases
journal, September 2010

  • DeMar, James C.; Clarkson, Edward D.; Ratcliffe, Ruthie H.
  • Chemico-Biological Interactions, Vol. 187, Issue 1-3
  • DOI: 10.1016/j.cbi.2010.02.015

High throughput artificial membrane permeability assay for blood–brain barrier
journal, March 2003

Syrian gas attack reinforces need for better anti-sarin drugs
journal, October 2013

In Vitro P-glycoprotein Assays to Predict the in Vivo Interactions of P-glycoprotein with Drugs in the Central Nervous System
journal, October 2007

  • Feng, Bo; Mills, Jessica B.; Davidson, Ralph E.
  • Drug Metabolism and Disposition, Vol. 36, Issue 2
  • DOI: 10.1124/dmd.107.017434

Novel oximes as blood–brain barrier penetrating cholinesterase reactivators
journal, September 2010

  • Garcia, Gregory E.; Campbell, Amy J.; Olson, John
  • Chemico-Biological Interactions, Vol. 187, Issue 1-3
  • DOI: 10.1016/j.cbi.2010.02.033

Human microdosing for the prediction of patient response
journal, March 2010

  • Henderson, Paul T.; Pan, Chong-xian
  • Bioanalysis, Vol. 2, Issue 3
  • DOI: 10.4155/bio.10.3

Elimination of Glyceryl Trinitrate: Effects of sex, age, Species and Route of Administration
journal, September 1982

Kinetic profile in blood and brain of the cholinesterase reactivating oxime HI-6 after intravenous administration to the rat
journal, November 1983

Human in Vivo Pharmacokinetics of [ 14 C]Dibenzo[ def,p ]chrysene by Accelerator Mass Spectrometry Following Oral Microdosing
journal, December 2014

  • Madeen, Erin; Corley, Richard A.; Crowell, Susan
  • Chemical Research in Toxicology, Vol. 28, Issue 1
  • DOI: 10.1021/tx5003996

Determining the Pharmacokinetics and Long-Term Biodistribution of SiO 2 Nanoparticles In Vivo Using Accelerator Mass Spectrometry
journal, October 2012

  • Malfatti, Michael A.; Palko, Heather A.; Kuhn, Edward A.
  • Nano Letters, Vol. 12, Issue 11
  • DOI: 10.1021/nl302412f

Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats
journal, August 2014

  • Malfatti, Michael A.; Lao, Victoria; Ramos, Courtney L.
  • Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 11
  • DOI: 10.1128/AAC.03300-14

Preclinical Studies of Noncharged Oxime Reactivators for Organophosphate Exposure: NONCHARGED OXIME REACTIVATORS
journal, August 2013

  • Okolotowicz, Karl J.; Dwyer, Mary; Smith, Emily
  • Journal of Biochemical and Molecular Toxicology, Vol. 28, Issue 1
  • DOI: 10.1002/jbt.21519

Report on 640 Victims of the Tokyo Subway Sarin Attack
journal, August 1996

Acute and chronic effects of sarin exposure from the Tokyo subway incident
journal, May 2005

  • Okumura, Tetsu; Hisaoka, Teruhiko; Naito, Toshio
  • Environmental Toxicology and Pharmacology, Vol. 19, Issue 3
  • DOI: 10.1016/j.etap.2004.12.005

The Tokyo subway sarin attack—lessons learned
journal, September 2005

Clinical evaluation of pesticide exposure and poisonings
journal, April 1997

Paraoxon has only a minimal effect on pralidoxime brain concentration in rats
journal, January 2007

  • Petroianu, G. A.; Lorke, D. E.; Hasan, M. Y.
  • Journal of Applied Toxicology, Vol. 27, Issue 4
  • DOI: 10.1002/jat.1213

Refinement of Structural Leads for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases
journal, February 2012

  • Radić, Zoran; Sit, Rakesh K.; Kovarik, Zrinka
  • Journal of Biological Chemistry, Vol. 287, Issue 15
  • DOI: 10.1074/jbc.M111.333732

Mechanism of interaction of novel uncharged, centrally active reactivators with OP-hAChE conjugates
journal, March 2013

  • Radić, Zoran; Sit, Rakesh K.; Garcia, Edzna
  • Chemico-Biological Interactions, Vol. 203, Issue 1
  • DOI: 10.1016/j.cbi.2012.08.014

Brain distribution spaces of mannitol-3H, inulin-14C, and dextran-14C in the rat
journal, July 1971

New Structural Scaffolds for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases
journal, April 2011

  • Sit, Rakesh K.; Radić, Zoran; Gerardi, Valeria
  • Journal of Biological Chemistry, Vol. 286, Issue 22
  • DOI: 10.1074/jbc.M111.230656

The role of excitotoxicity in organophosphorous nerve agents central poisoning
journal, June 1997

Accelerator Mass Spectrometry
journal, June 1995

  • Vogel, John S.; Turteltaub, Kenneth W.; Finkel, Robert
  • Analytical Chemistry, Vol. 67, Issue 11
  • DOI: 10.1021/ac00107a714

A Combined Accelerator Mass Spectrometry-Positron Emission Tomography Human Microdose Study with 14C- and 11C-Labelled Verapamil
journal, January 2011

    Sort by:
    [ × clear filter / sort ]

    Works referencing / citing this record:

    Oxime K203: a drug candidate for the treatment of tabun intoxication
    journal, December 2018

      Sort by:
      [ × clear filter / sort ]

      Similar Records in DOE PAGES and OSTI.GOV collections: