Theses and Dissertations
Advisor
Chambers, Janice E.
Committee Member
Carr, Russell
Committee Member
Howell, George E., III
Committee Member
Wills, Robert W.
Date of Degree
8-13-2024
Original embargo terms
Embargo 1 year
Document Type
Dissertation - Open Access
Major
Environmental Toxicology
Degree Name
Doctor of Philosophy (Ph.D.)
College
College of Veterinary Medicine
Department
Department of Comparative Biomedical Sciences
Abstract
Organophosphates (OPs) were initially designed as insecticides and later engineered as dangerous nerve agents that threaten our livelihood and safety. One of the treatments for OP exposure is the administration of an oxime to reactivate inhibited acetylcholinesterase (AChE). The currently approved oxime therapy in the US, pralidoxime (2-PAM), is unable to reactivate inhibited AChE in the brain due to its low ability to cross the blood-brain barrier (BBB) which has led our laboratory to develop novel substituted phenoxyalkyl pyridinium oximes (US Patent 9,227,937) that penetrate the BBB more effectively. Our lead oxime candidate, Oxime 20, has proven efficacious in reactivating inhibited AChE both in vitro and in vivo and is in the preliminary steps of drug development which require metabolism studies such as pharmacokinetics (PK), protein-binding (PB) and metabolite identification. PK parameters were explored for Oxime 20 and found to have an average half-life of 11.6 hours and an average Tmax of 0.083 hours in rats and an average half-life of 15 hours and an average Tmax of 0.11 hours in minipigs. As compared to 2-PAM, our oxime has displayed a 2-4 times longer half-life and a 3 times faster Tmax which allows it to be distributed at a faster rate and stay in circulation for longer. Furthermore, Oxime 20 was found to be >84% plasma protein-bound as compared to 2-PAM which was <8% protein-bound. These PB characteristics align with the PK parameters as highly protein-bound drugs tend to have a longer half-life than low protein-bound drugs. Finally, our oxime displayed a potentially safe metabolism in the presence of microsomes with the generation of two more polar metabolites as compared to Oxime 20, a hydroxyl metabolite and a carboxylic acid metabolite. With these findings, Oxime 20 continues to show promise and excellent characteristics for drug development and potentially will be the next suitable and effective option for treatment of OP exposure either by itself or in combination with 2-PAM.
Recommended Citation
Burke, Thomas Christopher, "The disposition and metabolism of a novel brain-penetrating oxime reactivator of inhibited acetylcholinesterase" (2024). Theses and Dissertations. 6332.
https://scholarsjunction.msstate.edu/td/6332