Title: Comparison of the toxicokinetics of the convulsants picrotoxinin and tetramethylenedisulfotetramine (TETS) in mice.

Authors: Pressly, Brandon; Vasylieva, Natalia; Barnych, Bogdan; Singh, Vikrant; Singh, Latika; Bruun, Donald A; Hwang, Sung Hee; Chen, Yi-Je; Fettinger, James C; Johnnides, Stephanie; Lein, Pamela J; Yang, Jun; Hammock, Bruce D; Wulff, Heike

Published In Arch Toxicol, (2020 06)

Abstract: Acute intoxication with picrotoxin or the rodenticide tetramethylenedisulfotetramine (TETS) can cause seizures that rapidly progress to status epilepticus and death. Both compounds inhibit γ-aminobutyric acid type-A (GABAA) receptors with similar potency. However, TETS is approximately 100 × more lethal than picrotoxin. Here, we directly compared the toxicokinetics of the two compounds following intraperitoneal administration in mice. Using LC/MS analysis we found that picrotoxinin, the active component of picrotoxin, hydrolyses quickly into picrotoxic acid, has a short in vivo half-life, and is moderately brain penetrant (brain/plasma ratio 0.3). TETS, in contrast, is not metabolized by liver microsomes and persists in the body following intoxication. Using both GC/MS and a TETS-selective immunoassay we found that mice administered TETS at the LD50 of 0.2 mg/kg in the presence of rescue medications exhibited serum levels that remained constant around 1.6 μM for 48 h before falling slowly over the next 10 days. TETS showed a similar persistence in tissues. Whole-cell patch-clamp demonstrated that brain and serum extracts prepared from mice at 2 and 14 days after TETS administration significantly blocked heterologously expressed α2β3γ2 GABAA-receptors confirming that TETS remains pharmacodynamically active in vivo. This observed persistence may contribute to the long-lasting and recurrent seizures observed following human exposures. We suggest that countermeasures to neutralize TETS or accelerate its elimination should be explored for this highly dangerous threat agent.

PubMed ID: 32239239

MeSH Terms: Animals; Biotransformation; Brain/drug effects*; Brain/metabolism; Brain/physiopathology; Bridged-Ring Compounds/pharmacokinetics; Bridged-Ring Compounds/toxicity*; Convulsants/pharmacokinetics; Convulsants/toxicity*; GABA Antagonists/pharmacokinetics; GABA Antagonists/toxicity*; Lethal Dose 50; Male; Mice; Picrotoxin/analogs & derivatives*; Picrotoxin/pharmacokinetics; Picrotoxin/toxicity; Receptors, GABA-A/metabolism; Seizures/chemically induced*; Seizures/metabolism; Seizures/physiopathology; Tissue Distribution; Toxicokinetics