Skov Louise, Holm Karen Marie Dollerup, Linnet Kristian
Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's Vej 11, DK-2100 Copenhagen Ø, Denmark.
Forensic Sci Int. 2016 Nov;268:39-45. doi: 10.1016/j.forsciint.2016.09.002. Epub 2016 Sep 12.
Reference concentrations are needed to evaluate postmortem toxicology results and usually femoral blood is the specimen of choice. However, brain tissue has been suggested as a viable alternative specimen, since postmortem blood concentrations can be difficult to interpret due to postmortem redistribution, among other factors. Here we present reference concentrations of postmortem brain and femoral blood of the nitrobenzodiazepines clonazepam, flunitrazepam, and nitrazepam that are of particular interest since they commonly are converted to their corresponding 7-aminometabolites in the postmortem situation. The drugs and metabolites were quantified in both matrices using LC-MS-MS in 69 cases. In 63 cases the compounds were judged not to have been of significance for the death (C cases), whereas they were considered to have been a contributing factor in 6 cases (B cases). No cases were observed with a nitrobenzodiazepine being the sole cause of death (A cases). The brain-blood ratios for clonazepam and nitrazepam were 5.5 and 4.7, respectively, while the brain-blood ratios for the 7-aminometabolites ranged from 0.4 to 0.5. Flunitrazepam only occurred as the 7-aminometabolite. A positive correlation between brain and blood concentrations was found with Spearman's rank correlation coefficients (r) ranging from 0.77 to 0.96. The measured femoral blood concentrations agree with literature values, but only few brain concentrations were available for comparison. The drug-metabolite ratios for clonazepam and nitrazepam were 10-12 times higher in brain than in blood. The pre-analytical variation in brain of 5.9% was fairly low, suggesting that brain tissue is a useful alternative to blood. The reported brain and femoral blood concentrations serve as reference values in postmortem investigations.
评估死后毒理学结果需要参考浓度，通常股静脉血是首选样本。然而，有人提出脑组织是一种可行的替代样本，因为除其他因素外，死后再分布会使死后血液浓度难以解释。在此，我们给出了氯硝西泮、氟硝西泮和硝西泮这几种硝基苯二氮䓬类药物死后脑组织和股静脉血的参考浓度，这些药物特别受关注，因为它们在死后通常会转化为相应的7-氨基代谢物。在69例病例中，使用液相色谱-串联质谱法对两种基质中的药物和代谢物进行了定量分析。在63例病例中，判断这些化合物对死亡无显著影响（C类病例），而在6例病例中，它们被认为是一个促成因素（B类病例）。未观察到硝基苯二氮䓬类药物是唯一死因的病例（A类病例）。氯硝西泮和硝西泮的脑血比分别为5.5和4.7，而7-氨基代谢物的脑血比在0.4至0.5之间。氟硝西泮仅以7-氨基代谢物的形式出现。发现脑浓度与血浓度之间存在正相关，Spearman等级相关系数（r）在0.77至0.96之间。测得的股静脉血浓度与文献值相符，但可供比较的脑浓度很少。氯硝西泮和硝西泮的药物代谢物比值在脑中比在血中高10至12倍。脑中5.9%的分析前变异相当低，表明脑组织是血液的有用替代物。报告的脑组织和股静脉血浓度可作为死后调查的参考值。
