Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, 57007, USA.
Analytical Toxicology Division, United States Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD, 21010, USA.
J Chromatogr A. 2019 Apr 26;1591:71-78. doi: 10.1016/j.chroma.2019.01.058. Epub 2019 Jan 23.
Cyanide is a rapidly acting and highly toxic chemical. It inhibits cytochrome c oxidase in the mitochondrial electron transport chain, resulting in cellular hypoxia, cytotoxic anoxia and potentially death. In order to overcome challenges associated with current cyanide antidotes, dimethyl trisulfide (DMTS), which converts cyanide to less toxic thiocyanate in vivo, has gained much attention recently as a promising next-generation cyanide antidote. While there are three analysis methods available for DMTS, they each have significant disadvantages. Hence, in this study, a dynamic headspace (DHS) gas chromatography-mass spectroscopy method was developed for the analysis of DMTS from rabbit whole blood. The method is extremely simple, involving only acidification of a blood sample, addition of an internal standard (DMTS-d) and DHS-GC-MS analysis. The method produced a limit of detection of 0.04 μM for DMTS with dynamic range from 0.2 to 50 μM. Inter- and intraassay accuracy (100 ± 15% and 100 ± 9%, respectively), and precision (<10% and <9% relative standard deviation, respectively) were good. The validated method performed well during pharmacokinetic analysis of DMTS from the blood of rats treated with DMTS, producing excellent pharmacokinetic parameters for the treatment of cyanide exposure. The method produced significant advantages over current methods for analysis of DMTS and should be considered as a "gold standard" method for further development of DMTS as a potential next-generation cyanide countermeasure.
氰化物是一种作用迅速且毒性极高的化学物质。它抑制线粒体电子传递链中的细胞色素 c 氧化酶，导致细胞缺氧、细胞毒性缺氧，并可能导致死亡。为了克服当前氰化物解毒剂所面临的挑战，二甲基三硫醚（DMTS）作为一种很有前途的下一代氰化物解毒剂，最近受到了广泛关注。虽然有三种分析 DMTS 的方法，但它们都有很大的缺点。因此，在这项研究中，开发了一种动态顶空（DHS）气相色谱-质谱法，用于分析兔全血中的 DMTS。该方法非常简单，仅涉及酸化血样、加入内标（DMTS-d）和 DHS-GC-MS 分析。该方法对 DMTS 的检测限为 0.04 μM，动态范围为 0.2 至 50 μM。该方法的批内和批间准确度（分别为 100 ± 15%和 100 ± 9%）和精密度（分别为<10%和<9%的相对标准偏差）均良好。该验证方法在 DMTS 治疗大鼠血液中 DMTS 的药代动力学分析中表现良好，为氰化物暴露的治疗提供了出色的药代动力学参数。与当前的 DMTS 分析方法相比，该方法具有显著优势，应被视为进一步开发 DMTS 作为潜在下一代氰化物对抗措施的“金标准”方法。
