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 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.

Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)

“…The huge number of OP poisoning cases and the big stocks of still available nerve agents in diverse countries make necessary the discovery of large OP broadspectrum antidotes [9][10][11][12]. Currently, the treatment procedure for OP poisoning consists of the use of two classes of drugs: competitive muscarinic receptor antagonist, such as atropine, and the use of a reactivating substance, usually one agent from the oxime class [13][14][15]. Unfortunately, there is no universal antidote to date, and a broad-spectrum oxime capable of reactivating all types of OPinhibited AChE/butyrylcholinesterase (BChE) is highly desired [15][16][17].…”

“…Currently, the treatment procedure for OP poisoning consists of the use of two classes of drugs: competitive muscarinic receptor antagonist, such as atropine, and the use of a reactivating substance, usually one agent from the oxime class [13][14][15]. Unfortunately, there is no universal antidote to date, and a broad-spectrum oxime capable of reactivating all types of OPinhibited AChE/butyrylcholinesterase (BChE) is highly desired [15][16][17]. In this review, the recent advances in the development of novel antidotes and therapies were analyzed according to the patents produced in the past few years.…”

Understanding the Interaction Modes and Reactivity of Trimedoxime toward MmAChE Inhibited by Nerve Agents: Theoretical and Experimental Aspects

“…The current treatment protocol for OP poisoning consists mainly of the employment of a reactivating agent, commonly an oxime compound [13][14][15][16], which is capable of restoring the AChE catalytic activity through a nucleophilic attack, thus remediating the intoxication effects and reestablishing the ACh levels [17][18][19]. The general reactivation mechanism through oximes is represented in Figure 1.…”

Understand the interaction modes and reactivity of trimedoxime toward MmAChE inhibited by nerve agents: theoretical and experimental Aspects

“…The current treatment protocol for OP poisoning consists mainly of the employment of a reactivating agent, commonly an oxime compound [13][14][15][16], which is capable of restoring the AChE catalytic activity through a nucleophilic attack, thus remediating the intoxication effects and reestablishing the ACh levels [17][18][19]. The general reactivation mechanism through oximes is represented in gure 1.…”

“…In view of the exposed so far, it is important to notice that there is no universal antidote to date, that is, a broad-spectrum oxime capable of reactivating all types of OP-inhibited AChE. In recent years, efforts have focused on the screening and identi cation of potent oximes, with su cient permeability through the blood-brain barrier (BBB), maintaining a high reactivation rate [19][20][21]. In this study, we present a theoretical and experimental investigation to better understand the reactivation mechanism of the AChE inhibited by several kinds of OP agents.…”