Skip Navigation



ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh012
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
77/2/358    most recent
kfh012v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Ashani, Y.
Right arrow Articles by Pistinner, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ashani, Y.
Right arrow Articles by Pistinner, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Received July 23, 2003; accepted October 2, 2003
© 2003 Society of Toxicology

Risk Assessment

Estimation of the Upper Limit of Human Butyrylcholinesterase Dose Required for Protection against Organophosphates Toxicity: A Mathematically-Based Toxicokinetic Model

Yacov Ashani 1 and Shlomi Pistinner 1*

1 Israel Institute for Biological Research, P.O. Box19, Ness Ziona, Israel

* To whom correspondence should be addressed. E-mail: shlomi{at}math.iibr.gov.il.


  Abstract

Human butyrylcholinesterase (HuBChE) is a drug candidate for protection against organophosphates (OP) intoxication. A mathematically-based model was validated and employed for purposes of better understanding the role of the endogenous HuBChE in detoxification of OPs, and estimation of the dose of exogenous HuBChE required for enhancing protection of humans from lethal exposure to OPs. The model addresses the relationship between the HuBChE dose needed to maintain a certain residual activity of human acetylcholinesterase (HuAChE) and the following parameters: (a) level and duration of exposure, (b) bimolecular rate constants of inhibition of HuAChE (kA) and HuBChE (kB) by OPs, and (c) time elapsed from enzyme load. The equation derived for the calculation of HuBChE dose requires the knowledge of kA/kB in human blood and the rate constant of HuBChE elimination. Predictions of HuBChE doses were validated by in vitro experiments and data of published human studies. These predictions highlight two parameters that are likely to decrease the calculated dose: The rapid consumption of the less toxic isomers of OPs in human plasma, and the volume of distribution of HuBChE that appears significantly greater than the volume of plasma. The first part of the analysis of the proposed model was focused on acute bolus exposures and suggests that upper limit doses of 134, 115 and 249 mg/70 kg are sufficient to protect RBC-AChE above 30% of baseline activity following a challenge with 1LD50 VX, soman, and sarin, respectively. The principles of the validated model should be applicable for advanced predictions of HuBChE dose for protection against continuous exposures to OPs.

Key Words: Human, Acetylcholinesterase, Butyrylcholinesterase, Organophosphates, Theoretical model, Inhibition .


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
N. Chilukuri, E. G. Duysen, K. Parikh, R. diTargiani, B. P. Doctor, O. Lockridge, and A. Saxena
Adenovirus-Transduced Human Butyrylcholinesterase in Mouse Blood Functions as a Bioscavenger of Chemical Warfare Nerve Agents
Mol. Pharmacol., September 1, 2009; 76(3): 612 - 617.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.