五种苯二氮卓类安眠药的体外代谢研究

发布时间：2019-02-15 03:46

【摘要】：苯二氮卓类安眠药属于中枢神经系统药物,是一类具有抗焦虑、抗癫痫、抗惊厥、催眠等药理作用的化合物,并可用于手术前麻醉。滥用该类安眠药将损害人体健康,严重时甚至损害人的大脑和中枢神经系统；不法分子利用该类安眠药对人类大脑和中枢神经系统的干预性,进行麻醉抢劫、强奸、诈骗等犯罪活动,给社会公共安全带来了严重的危害。药物的代谢是指药物在有机体内的生物转化过程。苯二氮卓类安眠药在生物体内半衰期短,代谢广泛,因此在生物检材中检出原体药物的概率很小。故研究苯二氮卓类安眠药在生物体内的代谢,鉴定其代谢产物,进而推断其在体内的代谢途径,对临床医学检验及法庭科学具有重要的意义。本论文以人体和大鼠肝微粒体为体外代谢模型,使用先进的分析技术：固相萃取,气相色谱-质谱联用和高效液相色谱-线性离子阱质谱联用等研究了五种苯二氮卓类安眠药安定、利眠宁、硝基安定、氯硝安定、三唑仑在人体和大鼠肝微粒体中的代谢,通过与前期体内代谢研究及部分标准品比对等,解析和推断了其在人体和大鼠体内的代谢产物和代谢途径,得到了10种文献未曾报道的代谢产物：7-氯-2-甲氧基-5-苯基-3H-1,4-苯二氮卓、5-(4-羟基苯基)-氯硝安定、去甲三唑仑、去甲-5-N-氧化三唑仑、去甲-6-(4-羟基苯基)-5-N-氧化三唑仑、6-(4-羟基苯基)-三唑仑、(2-N-氧化三唑环)-5-N-氧化三唑仑、6-(4-羟基苯基)-5-N-氧化三唑仑、α-羟基-5-N-氧化三唑仑和α-羟基-6-(4-羟基苯基)-三唑仑,完善了安定、利眠宁、硝基安定、氯硝安定、三唑仑等苯二氮卓类安眠药的代谢研究。同时建立了在线固相萃取结合高效液相色谱-线性离子阱质谱法测定血液和尿液中19种苯二氮卓类安眠药及其代谢物的方法。建立了50种常见毒品毒物及其代谢物的LC-MS的二级和三级质谱数据库,并应用于生物检材中实际样品的快速筛查及其定性,可以提供较好的匹配率。本论文的研究,对医药科学有着广阔的应用前景,更对临床医学检验及法庭科学具有重要的意义,为打击相关的犯罪活动提供了有力的参考。
[Abstract]:Benzodiazepines are a kind of central nervous system drugs, which have anti-anxiety, antiepileptic, anticonvulsive, hypnotic and other pharmacological effects, and can be used in preoperation anesthesia. Abuse of such sleeping pills will harm human health, and even damage the human brain and central nervous system when serious; The lawless elements make use of these sleeping pills to interfere with the human brain and central nervous system and carry on the crime activities such as narcotic robbery rape fraud and so on which bring serious harm to the social public safety. Drug metabolism refers to the biological transformation of drugs in organic bodies. Benzodiazepines have short half-life and extensive metabolism in vivo, so the probability of detection of mycoplasma in biological samples is very small. Therefore, it is of great significance for clinical medical examination and forensic science to study the metabolism of benzodiazepines in vivo, identify their metabolites and infer their metabolic pathways in vivo. In this paper, human and rat liver microsomes were used as metabolic models in vitro, and advanced analytical techniques were used: solid phase extraction (SPE), solid phase extraction (SPE), The metabolism of diazepam, nitrodiazepam, clonidazepam and triazolam in human body and rat liver microsomes were studied by gas chromatography-mass spectrometry and high performance liquid chromatography-linear ion trap mass spectrometry. The metabolic products and pathways in human body and in rats were analyzed and inferred by comparison with the previous studies of metabolism in vivo and comparison of some standard products. Ten metabolites unreported in the literature were obtained: 7-chloro-2-methoxy-5-phenyl-3H-1- (4-benzodiazepine), 5- (4-hydroxyphenyl) -clonazepam, nortriazolam, nor-5-N- triazolam oxide. Nor-6- (4-hydroxyphenyl) -5-N-triazolam oxide, 6- (4-hydroxyphenyl) -triazolam, (2-N- triazolam oxide) -5-N- triazolam oxide, 6- (4-hydroxyphenyl) -5-N- triazolam oxide, 伪 -hydroxy-5-N- triazolam oxide and 伪 -hydroxy-6- (4-hydroxyphenyl) -triazolam, which have improved diazepam, limonin, nitrodiazepam, clonazepam, Study on metabolism of triazolam and benzodiazepines. A method for the determination of 19 benzodiazepines and their metabolites in blood and urine by high performance liquid chromatography-linear ion trap mass spectrometry was established. The secondary and tertiary mass spectrometry databases of LC-MS for 50 common drug poisons and their metabolites were established and applied to the rapid screening and qualitative analysis of actual samples in biological samples, which can provide a good matching rate. The research of this paper has a broad application prospect to the medicine science, also has the important significance to the clinical medical examination and the court science, has provided the powerful reference for the fight against the related criminal activity.
【学位授予单位】：广西大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96

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