Investigation of blood-brain barrier penetration and pharmacokinetics of a new formulation of cyanide antidote dimethyl trisulfide.

Abstract

Objective: During cyanide poisoning, the rescue of vital organs like the brain is urgent. However, due to the presence of the blood-brain barrier (BBB), the currently available cyanide antidotes cannot reach the brain. Dimethyl trisulfide (DMTS) is a potent cyanide antidote and has excellent BBB permeability. Nonetheless, its formulation and application are challenging due to its highly lipophilic profile. In this work, a novel DMTS formulation, called FF-DMTS, was investigated. Its effect on in vitro DMTS permeability through BBB models, cellular viability, and in vivo absorption were tested.

Methods: The particle size was measured in FF-DMTS formulation. The permeability of DMTS in this new formulation was tested in BBB-PAMPA and in primary triple co-culture models of BBB. The effect of FF-DMTS on cellular viability was determined. To test the membrane and barrier integrity transendothelial electrical resistance (TEER) and cell layer impedance measurements, immunofluorescent stainings and the fluorescein permeability technique were applied. The pharmacokinetics of DMTS were revealed in blood and brain tissue.

Results: The average size of micelles in FF-DMTS was 16 nm. The permeability of DMTS through BBB-PAMPA and cell culture model was 7.68 × 10^-6 and 23.81 × 10^-6 cm/s, respectively. The FF-DMTS disturbed the barrier integrity of brain endothelial cells without causing any alteration in cellular viability until 300 µg/ml DMTS concentration. After administration of 150 mg/kg DMTS to mice, its absorption into the blood was rapid (5 min) and the plasma concentration of DMTS reached 5.2 µg/ml. The DMTS was also detected in brain, where its peak concentration was 495 ng/g brain tissue after 10 min of intramuscular administration. Furthermore, even 2 h later, DMTS was detected in brain.

Conclusions: Here, we showed that the novel FF-DMTS formulation has good permeability through BBB and a remarkable pharmacokinetic profile. Therefore, further investigation of the efficacy of FF-DMTS for treating cyanide intoxication is important.