本文選題：新型抗抑郁藥 + 超聲輔助低密度溶劑分散液液微萃取��； 參考：《福建中醫(yī)藥大學(xué)》2017年碩士論文

【摘要】：抑郁癥是一種常見的精神疾病,主要特征為心境低落、思維遲緩等,嚴(yán)重者會出現(xiàn)自殺行為。新型抗抑郁藥是目前臨床上用于治療抑郁癥的主導(dǎo)藥物。但隨著新型抗抑郁藥的使用不斷增加,出現(xiàn)了藥物濫用及被應(yīng)用于暴力犯罪中等情況,此外,臨床上存在藥物聯(lián)用,但對于藥物的相互作用研究尚少。針對這些存在的問題,本課題研究了該類藥物的快速定量方法、在生物體內(nèi)的藥物代謝情況及與其他抗精神病藥物聯(lián)用的體內(nèi)相互影響,為新型抗抑郁藥的用藥安全、法醫(yī)鑒定、基礎(chǔ)研究及臨床研究提供技術(shù)手段和參考依據(jù)。具體的研究內(nèi)容如下:1超聲輔助-低密度溶劑-分散液液微萃取GC/MS法同時測定人全血中12種新型抗抑郁藥和2種常用抗精神病藥以超聲輔助-低密度溶劑-分散液液微萃取(UA-LDS-DLLME)技術(shù)進(jìn)行人全血的樣品前處理,建立了 12種新型抗抑郁藥與2種常用的抗精神病藥物同時定量的方法。12種新型抗抑郁藥分別為諾氟西汀、氟西汀、氟伏沙明、阿戈美拉汀、米氮平、嗎氯貝胺、美利曲辛、去甲米氮平、馬普替林、舍曲林、西酞普蘭和帕羅西汀,2種抗精神病藥物為氯氮平和氟哌啶醇。對人全血的UA-LDS-DLLME前處理方法進(jìn)行優(yōu)化,確立了最優(yōu)條件:以100μL甲苯為萃取劑,加入100 μLpH12的氨水,超聲3min。GC/MS的測定條件為:色譜柱:DB-5ms(0.25mm×3.0m×0.25 μm),不分流進(jìn)樣,進(jìn)樣時間為1min,進(jìn)樣口溫度280℃;柱箱升溫程序:100℃(1 min)_20℃/min_20℃(5min)_8℃/min_300℃(5min)。EI電子轟擊源,70eV;離子源溫度23℃;接口溫度300℃,.溶劑延遲4min;選擇離子掃描模式。選用諾氟西汀-D6和帕羅西汀-D6為內(nèi)標(biāo)。方法學(xué)驗(yàn)證結(jié)果表明該方法具有專屬性,14個待測化合物分別在15-1500 ng/mL或5-500 ng/mL范圍內(nèi)線性良好(r20.99),日內(nèi)(n=5)及日間(n=15)的準(zhǔn)確度和精密度均符合規(guī)定要求(準(zhǔn)確度在±15%以內(nèi),精密度小于15%),大部分化合物的提取回收率在50%以上,穩(wěn)定性良好。該方法已成功應(yīng)用于實(shí)際案例中。2基于液相色譜-高分辨質(zhì)譜(LC-HRMS)的新型抗抑郁藥美利曲辛在大鼠體內(nèi)的代謝研究建立了基于UHPLC/LTQ-Orbitrap的LC-HRMS聯(lián)用方法,通過結(jié)合精確質(zhì)量數(shù)和多級碎片離子信息,研究抗抑郁藥美利曲辛在大鼠體內(nèi)的代謝產(chǎn)物與代謝途徑。以美利曲辛灌胃給藥大鼠,收集大鼠給藥前及給藥后的3、6、9、12、24h各時間段的尿液用于分析,分別采用固相萃取和液液萃取進(jìn)行樣品前處理,最終在大鼠尿液中找到美利曲辛及其Ⅰ相和Ⅱ相代謝物共30種,并初步推斷了美利曲辛在大鼠體內(nèi)的代謝途徑主要為去甲基和羥基化。3大鼠血漿中度洛西汀和喹硫平的LC-MS/MS法測定及藥代動力學(xué)研究建立了同時測定大鼠血漿中度洛西汀和喹硫平的LC-MS/MS定量方法,采用蛋白沉淀法處理血漿。采用EclipseXDB-C18柱,流動相A為含2 mmol/L甲酸銨和0.1%甲酸的水相,流動相B為含2mmol/L甲酸銨和0.1%甲酸的乙腈有機(jī)相,采用梯度洗脫,分析時間為6.0 min。質(zhì)譜采用MRM模式,化合物與內(nèi)標(biāo)的離子對分別為:度洛西汀m/z 298.1→154.1,喹硫平 m/z 384.4→253.2,內(nèi)標(biāo)(氟哌啶醇)m/z 376.2→165.2。經(jīng)方法學(xué)驗(yàn)證,該法具有專屬性,度洛西汀和喹硫平的定量下限分別為0.500 ng/mL和1.00 ng/mL,在0.500～100 ng/mL和1.00～200 ng/mL范圍內(nèi)線性關(guān)系良好,準(zhǔn)確度和精密度均在允許的范圍內(nèi),提取回收率均會87.7%,總體內(nèi)標(biāo)歸一化的基質(zhì)效應(yīng)為1.03和0.94,能滿足生物樣品的分析要求。將此方法成功應(yīng)用于度洛西汀與喹硫平聯(lián)合用藥的藥代動力學(xué)研究,將SD大鼠隨機(jī)分為3組,每組6只,分別進(jìn)行單一給藥度洛西汀、單一給藥喹硫平及聯(lián)合給藥度洛西汀和喹硫平,通過藥代動力學(xué)參數(shù)來評價合并用藥后的相互影響。度洛西汀的單一給藥組和聯(lián)合用藥組的Cmax和AUC0-∞分別為34.4 ± 5.6 ng/mL、372.7 ± 105.9 h-ng/mL和55.9 ± 13.0 ng/mL、544.1 ± 56.0 h·ng/mL。喹硫平的單一給藥組和聯(lián)合用藥組的Cmax和AUC0-∞分別為 18.1 ±14.6 ng/mL、35.2±35.0h·ng/mL 和 22.8± 15.5 ng/mL、41.2±21.1 h·ng/mL;經(jīng)過配對t檢驗(yàn),喹硫平的單一給藥組和聯(lián)合給藥組的Cmax和AUC0-∞的,P值均大于0.05,說明聯(lián)合用藥對喹硫平的藥代動力學(xué)無明顯影響;而度洛西汀的兩組間的Cmax和AUC0-∞的P值分別為0.016和0.039,AUC0-t的P值為0.001,說明聯(lián)合用藥對度洛西汀的藥代動力學(xué)有明顯影響,喹硫平能增加度洛西汀在大鼠體內(nèi)的血藥濃度,其藥代動力學(xué)參數(shù)Cmax和AUC明顯增大。
[Abstract]:Depression is a common mental illness, characterized by low mood, slow thinking, and serious mental retardation. The new antidepressant is the dominant drug used in the treatment of depression, but with the increasing use of new antidepressants, drug abuse and the medium of use of violent crimes have emerged. In addition, there are clinical drugs in combination, but there are few studies on the interaction of drugs. In view of these problems, we have studied the rapid quantitative methods of the drugs, the drug metabolism in the organism and the interaction with other antipsychotic drugs in vivo, and the safety of the new antidepressant drugs and the forensic evaluation. The basic research and clinical research provide technical means and reference basis. The specific research contents are as follows: 1 ultrasonic assisted low density solvent dispersible liquid liquid microextraction GC/MS method for simultaneous determination of 12 new antidepressants and 2 common antipsychotics in human whole blood with ultrasonic assisted low density solvent dispersible liquid microextraction (UA-LDS-DLLME) technique 12 new antidepressants, 12 new antidepressants and 2 commonly used antipsychotics, were established for the simultaneous determination of the whole blood samples. The new antidepressants were norfluoxetine, fluoxetine, Hide Saki, ametaline, Mi Danping, mopectrine, and meritactyine, to Krabi, mopecin, sertraline, and citalopram. And Pa Rossi Dean, 2 kinds of antipsychotic drugs were clozapine and haloperidol. The optimal conditions for UA-LDS-DLLME pretreatment of human whole blood were optimized. The optimum conditions were established: 100 u L toluene as extractant and 100 mu LpH12 of ammonia water. The ultrasonic 3min.GC/MS was determined by the chromatographic column: DB-5ms (0.25mm x 3.0m x 0.25 mu), without diversion and injection. The room temperature was 1min, the inlet temperature was 280 C; the column box heating program: 100 C (1 min) _20 C /min_20 C (5min) _8 C /min_300 (5min).EI electron bombardment source, 70eV, the temperature of the ion source 23, the interface temperature 300, the solvent delay 4min; the selective ion scanning mode. The method has special properties. The 14 compounds to be tested are linear in the range of 15-1500 ng/mL or 5-500 ng/mL respectively (r20.99). The accuracy and precision of intraday (n=5) and day (n=15) are all in accordance with the requirements (accuracy is within + 15%, precision is less than 15%). The extraction recovery of most compounds is above 50%, and the stability is good. The method has been proved to be good. Successfully applied to practical cases,.2 based on the metabolism of a new antidepressant,.2, based on liquid chromatography high resolution mass spectrometry (LC-HRMS), established a LC-HRMS combined method based on UHPLC/LTQ-Orbitrap. By combining accurate mass number and multilevel fragment ion information, the antidepressant, Meili, was studied in rats. The metabolites and metabolic pathways were administered to the rats by gastric perfusion, and the urine of the rats was collected before and after the administration of the 3,6,9,12,24h. Solid phase extraction and liquid extraction were used for sample pretreatment respectively. In the end, 30 kinds of metabolites were found in the urine of rats and their phase I and II phase. The metabolic pathways of milleine in rats were determined mainly by the LC-MS/MS determination and pharmacokinetics of moderate levioxetine and quetiapine in the plasma of.3 rats. A quantitative method for the simultaneous determination of the moderate levels of luoxetine and quetiapine in rat plasma was established, and plasma was treated by protein precipitation method, and EclipseXDB-C was used for the treatment of plasma. The 18 column, the mobile phase A is the aqueous phase of 2 mmol/L ammonium formate and 0.1% formic acid, and the mobile phase B is the organic phase of acetonitrile containing 2mmol/L formate and 0.1% formic acid. The gradient elution is used, the analysis time is 6 min. mass spectrometry using MRM mode, the compound and the internal standard ion pair are respectively dloxetine m /z 298.1 - 154.1, quetiapine m/z 384.4 to 253.2, internal standard (fluorine) Piperidine) m/z 376.2 to 165.2. is verified by square jurisprudence. This method has special properties. The quantitative lower limit of duloxetine and quetiapine is 0.500 ng/mL and 1 ng/mL respectively. The linear relationship is good in the range of 0.500 ~ 100 ng/mL and 1 to 200 ng/mL. The accuracy and precision are within the allowable range, and the recovery rate will be 87.7% and the overall standard is classified. The matrix effect of one chemical was 1.03 and 0.94, which could satisfy the analysis requirements of biological samples. The method was successfully applied to the pharmacokinetics study of duloxetine and quetiapine. The SD rats were randomly divided into 3 groups, 6 rats in each group, single administration of quinoline, single dose quetiapine and combined duloxetine and quetiapine, The Cmax and AUC0- infinity of the single drug group and the combination group of duloxetine were 34.4 + 5.6 ng/mL, 372.7 + 105.9 h-ng/mL and 55.9 + 13 ng/mL, 544.1 + 56 h ng/mL. quetiapine, and Cmax and AUC0- infinity of the combined drug group respectively. 18.1 + 14.6 ng/mL, 35.2 + 35.0h / ng/mL and 22.8 + 15.5 ng/mL, 41.2 + 21.1 H. Ng/mL. After paired t test, the Cmax and AUC0- infinity of the quetiapine group and the combined administration group were all greater than 0.05, indicating that the combined medication had no obvious effect on the pharmacokinetics of quetiapine, while the Cmax and AUC0- infinity between the two groups of duloxetine were found. The values were 0.016 and 0.039 respectively, and the P value of AUC0-t was 0.001, which indicated that the combined use of drugs had a significant effect on the pharmacokinetics of duloxetine. Quetiapine could increase the concentration of blood drug in rats, and the pharmacokinetic parameters of Cmax and AUC were significantly increased.
【學(xué)位授予單位】：福建中醫(yī)藥大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R96

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