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Pharmacokinetic Analysis of Ionizable Zwitterionic Oximes: Antidotes to Organophosphate Exposure.
Author(s) -
Samskey Nathan,
Ho Kwok-Yiu,
Momper Jeremiah,
Radic Zoran,
Sit Rakesh,
Sharpless K. Barry,
Taylor Palmer
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06319
Subject(s) - chemistry , antidote , pharmacology , nerve agent , pharmacokinetics , blood–brain barrier , cholinesterase , bioavailability , pyridinium , acetylcholinesterase , toxicity , biochemistry , medicine , central nervous system , enzyme , organic chemistry , medicinal chemistry , endocrinology
Currently approved antidotes to organophosphate (OP) exposure rely on discoveries of Irwin Wilson in the 1950’s, employing site‐directed pyridinium aldoximes to reactivate OP‐conjugated acetyl‐cholinesterase (AChE). This led to approval of 2‐PAM in the US and other pyridinium aldoximes elsewhere as antidotes to exposures of OP pesticides and terrorism nerve agents. However, principal limitations of these quaternary agents reside in their inability to cross the blood‐brain barrier and reactivate CNS AChE rapidly and their inherently rapid overall body clearance. Moreover, certain pyridinium aldoximes carry risks of channel blocking side effects. Alternative compounds that are ionizable zwitterions (hydroxyiminoacetamido alkyl amines‐RS194B) show facile transfer across the blood‐brain barrier through its neutral species, limited reversible binding to OP conjugated AChE, oral bioavailability and minimal toxicity. However, high doses may be needed for acute treatment, since these agents are extruded by brain capillary transporters and are rapidly cleared as the parent compound by renal transporters. To understand and counter these actions, we employed two approaches: (a) examination of tissue disposition and pharmacokinetics in a P‐glycoprotein knock‐out strain of mice, and (b) employing small molecules to inhibit extrusion of RS194B by brain capillaries and limit rapid clearance by renal tubules. While gene knock‐out enhances brain levels in mice, this is not practical in humans, so antidote retention in the CNS and diminishing renal clearance require competing small molecules. To avoid an imposed requirement of approval of two new agents, the antidote and a clearance inhibitor, we examined current FDA‐approved drugs for repurposing in a formulation. We have achieved favorable outcomes with transport inhibitors already approved by the FDA for other therapeutic purposes. Our approach employs agents that are zwitterionic, block P‐glycoprotein transport in the CNS and kidney, and show limited liability or toxicity for short term use. We have compared various fluoroquinolones, biguanides, ion channel blockers and have achieved favorable ratios of enhanced CNS levels and diminished renal clearance of RS194B in rodents at doses not eliciting toxicity. These comparisons enable assessing efficacy of the combination in other animal species. Support or Funding Information (Supported in part by RO1 GM18360 and UO1 NS058046)