In Vitro and In Vivo Blood-Brain Barrier Penetration Studies with the Novel Cyanide Antidote Candidate Dimethyl Trisulfide in Mice

Kiss, L. and Bocsik, Alexandra and Walter, Fruzsina and Ross, J. and Brown, D. and Sipos, Péter and Szabó-Révész, Piroska and Deli, Mária Anna and Petrikovics, Ilona (2017) In Vitro and In Vivo Blood-Brain Barrier Penetration Studies with the Novel Cyanide Antidote Candidate Dimethyl Trisulfide in Mice. TOXICOLOGICAL SCIENCES, 160 (2). pp. 398-407. ISSN 1096-6080

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Abstract

Recent in vitro and in vivo studies highlight the strong potential of dimethyl trisulfide (DMTS) as an antidote for cyanide (CN) intoxication. Due to its high oxygen demand, the brain is one of the main target organs of CN. The blood-brain barrier (BBB) regulates the uptake of molecules into the brain. In the literature, there is no data about the ability of DMTS to penetrate the BBB. Therefore, our aim was to test the in vitro BBB penetration of DMTS and its in vivo pharmacokinetics in blood and brain. The in vitro BBB penetration of DMTS was measured by using a parallel artificial membrane permeability assay (BBB-PAMPA), and a triple BBB co-culture model. The pharmacokinetics was investigated in a mouse model by following the DMTS concentration in blood and brain at regular time intervals following intramuscular administration. DMTS showed high penetrability in both in vitro systems (apparent permeability coefficients: BBB-PAMPA 11.8 x 10(-6) cm/s; cell culture 158 x 10(-6) cm/s) without causing cell toxicity and leaving the cellular barrier intact. DMTS immediately absorbed into the blood after the intramuscular injection (5 min), and rapidly penetrated the brain of mice (10 min). In addition to the observed passive diffusion in the in vitro studies, the contribution of facilitated and/or active transport to the measured high permeability of DMTS in the pharmacokinetic studies can be hypothesized. Earlier investigations demonstrating the antidotal efficacy of DMTS against CN together with the present results highlight the promise of DMTS as a brain-protective CN antidote.

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