【摘要】：苯二氮卓類安眠藥屬于中樞神經(jīng)系統(tǒng)藥物,是一類具有抗焦慮、抗癲癇、抗驚厥、催眠等藥理作用的化合物,并可用于手術(shù)前麻醉。濫用該類安眠藥將損害人體健康,嚴(yán)重時(shí)甚至損害人的大腦和中樞神經(jīng)系統(tǒng)；不法分子利用該類安眠藥對(duì)人類大腦和中樞神經(jīng)系統(tǒng)的干預(yù)性,進(jìn)行麻醉?yè)尳�、�?qiáng)奸、詐騙等犯罪活動(dòng),給社會(huì)公共安全帶來(lái)了嚴(yán)重的危害。 藥物的代謝是指藥物在有機(jī)體內(nèi)的生物轉(zhuǎn)化過(guò)程。苯二氮卓類安眠藥在生物體內(nèi)半衰期短,代謝廣泛,因此在生物檢材中檢出原體藥物的概率很小。故研究苯二氮卓類安眠藥在生物體內(nèi)的代謝,鑒定其代謝產(chǎn)物,進(jìn)而推斷其在體內(nèi)的代謝途徑,對(duì)臨床醫(yī)學(xué)檢驗(yàn)及法庭科學(xué)具有重要的意義。 本論文以人體和大鼠肝微粒體為體外代謝模型,使用先進(jìn)的分析技術(shù)：固相萃取,氣相色譜-質(zhì)譜聯(lián)用和高效液相色譜-線性離子阱質(zhì)譜聯(lián)用等研究了五種苯二氮卓類安眠藥安定、利眠寧、硝基安定、氯硝安定、三唑侖在人體和大鼠肝微粒體中的代謝,通過(guò)與前期體內(nèi)代謝研究及部分標(biāo)準(zhǔn)品比對(duì)等,解析和推斷了其在人體和大鼠體內(nèi)的代謝產(chǎn)物和代謝途徑,得到了10種文獻(xiàn)未曾報(bào)道的代謝產(chǎn)物：7-氯-2-甲氧基-5-苯基-3H-1,4-苯二氮卓、5-(4-羥基苯基)-氯硝安定、去甲三唑侖、去甲-5-N-氧化三唑侖、去甲-6-(4-羥基苯基)-5-N-氧化三唑侖、6-(4-羥基苯基)-三唑侖、(2-N-氧化三唑環(huán))-5-N-氧化三唑侖、6-(4-羥基苯基)-5-N-氧化三唑侖、α-羥基-5-N-氧化三唑侖和α-羥基-6-(4-羥基苯基)-三唑侖,完善了安定、利眠寧、硝基安定、氯硝安定、三唑侖等苯二氮卓類安眠藥的代謝研究。同時(shí)建立了在線固相萃取結(jié)合高效液相色譜-線性離子阱質(zhì)譜法測(cè)定血液和尿液中19種苯二氮卓類安眠藥及其代謝物的方法。建立了50種常見(jiàn)毒品毒物及其代謝物的LC-MS的二級(jí)和三級(jí)質(zhì)譜數(shù)據(jù)庫(kù),并應(yīng)用于生物檢材中實(shí)際樣品的快速篩查及其定性,可以提供較好的匹配率。本論文的研究,對(duì)醫(yī)藥科學(xué)有著廣闊的應(yīng)用前景,更對(duì)臨床醫(yī)學(xué)檢驗(yàn)及法庭科學(xué)具有重要的意義,為打擊相關(guān)的犯罪活動(dòng)提供了有力的參考。
[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, 偽 -hydroxy-5-N- triazolam oxide and 偽 -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.
【學(xué)位授予單位】：廣西大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R96

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