本文選題：鹽酸右美托咪定 + 肥胖患者　； 參考：《南方醫(yī)科大學(xué)》2014年碩士論文

【摘要】：鹽酸右美托咪定(Dexmedetomidine hydrochloride, Dex)化學(xué)名：(R)-4-[1-(2,3-二甲苯基)乙基]-1H-咪唑單鹽酸鹽,最早于2000年3月在美國上市,2008年進(jìn)入中國市場,作為一種高選擇性的α2-腎上腺素受體激動劑,其親和力比可樂定高8倍。因具有抑制交感神經(jīng)活性、鎮(zhèn)靜催眠、抗焦慮和鎮(zhèn)痛等作用,且不良反應(yīng)少,已廣泛應(yīng)用于圍術(shù)期鎮(zhèn)靜、鎮(zhèn)痛等領(lǐng)域[1]。關(guān)于該藥血藥濃度的測定方法國內(nèi)鮮有報道[2-3],國外有采用氣相色譜串聯(lián)質(zhì)譜法[4]、高效液相色譜串聯(lián)質(zhì)譜法(High performance liquid chromatography tandem mass spectrometry, HPLC-MS/MS)[5-7]、放射法[8]等,此類方法能檢測的最低濃度為5ng-L-1。樣品前處理方法有蛋白沉淀法[2]、液液萃取法[3、7]和固相萃取法[5]等。本試驗在此基礎(chǔ)上采用Agilent6410建立并驗證了樣品經(jīng)液液萃取后測定人血漿樣品中Dex濃度的HPLC-MS/MS法。肥胖患者每千克體質(zhì)量肌肉組織更少,脂肪組織更多。一般情況流入脂肪組織的血流量較少,約占心輸出量的5%,而流入內(nèi)臟的血流則占73%,肌肉為22%[9],如果按照總體重來增加藥物的劑量將會導(dǎo)致某些組織灌注血液中藥物濃度增加,最終導(dǎo)致血漿藥物相對過剩,不良反應(yīng)增加。到目前為止,尚未見有關(guān)Dex在全麻肥胖患者體內(nèi)的藥代動力學(xué)特征,因此我們將探索出來的HPLC-MS/MS法用于檢測全麻肥胖患者血漿中Dex的濃度,闡明Dex靜脈泵注后在肥胖患者體內(nèi)的藥代動力學(xué)特性,為臨床研究和更合理應(yīng)用Dex提供參考。 目的 一、建立HPLC-MS/MS測定人血漿Dex濃度； 二、全麻狀態(tài)下肥胖患者Dex的臨床藥代動力學(xué)特征。方法 一、建立HPLC-MS/MS法測定人血漿Dex濃度： ①質(zhì)譜分析：待測物Dex和內(nèi)標(biāo)替米沙坦在正離子檢測方式下,采用電噴霧離子源(ESI源),分子掃描分別為m/z201.1和m/z512.2。對準(zhǔn)分子離子選擇性地進(jìn)行產(chǎn)物離子全掃描分析,獲得Dex的主要碎片為m/z95.1,響應(yīng)值較高,且比較穩(wěn)定,背景噪音小,因此被選做多反應(yīng)監(jiān)測模式(MRM)定量分析的產(chǎn)物離子,用于定量分析。替米沙坦生產(chǎn)的主要產(chǎn)物碎片離子為m/z276.1,將其作為定量分析時監(jiān)測的產(chǎn)物離子。探索出來的質(zhì)譜QQQ條件為：毛細(xì)管電壓4000V,噴霧氣壓力45psi,干燥氣體流速10L·min-1,干燥氣體溫度350℃。 ②色譜條件：色譜柱選用美國Agilent Eclipse Plus C18(4.6mm×150mm,3.5μm)；流動相為甲醇：1%甲酸水(75：25,V/V)；流速為0.5ml·min-1;柱溫為35℃；進(jìn)樣量為2μ1。 ③血漿樣品的處理方法：精密加入血漿樣品200μ1置于10ml的玻璃離心管中,加入640ng·ml-1的替米沙坦甲醇溶液10μ1,加0.2mo1·L-1氫氧化鈉溶液100μ1,快速振蕩1分鐘,再加入乙酸乙酯：二氯甲烷(4：1液)1ml加蓋密封,旋渦振蕩2分鐘,2800r·min-1離心10分鐘,吸取有機(jī)層800μ1置錐形玻璃離心管內(nèi),30℃水浴鍋氮氣揮干。進(jìn)樣前加入殘渣溶解液(甲醇：水=80：20)100μl,快速振蕩30秒使殘渣溶解,吸到1.5ml離心管中,20000r·min-1離心5分鐘,吸取上清液2μ1進(jìn)樣。 ④標(biāo)準(zhǔn)曲線：分別配置Dex濃度為0、20、50、100、200、500、1000、2000、4000和6000ng·L-1的血漿樣品,按照“血漿樣品的處理方法”,經(jīng)HPLC-MS/MS分析,以Dex峰面積與內(nèi)標(biāo)峰面積之比(Y)為縱坐標(biāo),血漿中Dex濃度與內(nèi)標(biāo)濃度之比(X)為橫坐標(biāo),得出20-6000ng·L-1濃度范圍內(nèi)的標(biāo)準(zhǔn)曲線。 ⑤方法確證：包括專屬性、標(biāo)準(zhǔn)曲線、定量下限、精密度、回收率、介質(zhì)效應(yīng)和穩(wěn)定性研究。專屬性：對于色譜法至少要考察6個不同個體的空白生物樣本色譜圖、空白生物樣品外加對照物色譜圖(注明濃度)及用藥后的生物樣品色譜圖。標(biāo)準(zhǔn)曲線：一般用回歸分析法(如用加權(quán)最小二乘法等)所得的回歸方程來評價,必須至少用6個濃度建立標(biāo)準(zhǔn)曲線,定量范圍要能覆蓋全部待測的生物樣品濃度范圍,不得用定量范圍外推的方法求算未知樣品的濃度。定量下限：應(yīng)能滿足測定經(jīng)3-5個消除半衰期時樣品中的藥物濃度或能檢測出Cmax的1/10-1/20的藥物濃度范圍內(nèi),相對標(biāo)準(zhǔn)差(RSD)應(yīng)小于20%,其準(zhǔn)確度應(yīng)在真實濃度的80%-120%,至少應(yīng)由5個標(biāo)準(zhǔn)樣品測試結(jié)果證明；精密度：分別配制低(50ng·L-1)、中(500ng·L-1)和高濃度(4000ng·L-1)的Dex血漿質(zhì)控樣本各15份,分為3批,每批5份,并與每批的標(biāo)準(zhǔn)曲線同時進(jìn)行,計算質(zhì)控樣品的測得濃度,與配制濃度對照,求得本法的精密度；回收率：空白血漿除了不加內(nèi)標(biāo)外,經(jīng)“血漿樣品的處理方法”處理后,再加入相應(yīng)濃度的Dex和替米沙坦,以每一濃度兩種處理方法的峰面積比值計算提取回收率,采用1天的數(shù)據(jù),將Dex峰面積和內(nèi)標(biāo)峰面積的比值帶入隨行標(biāo)準(zhǔn)曲線,計算所得濃度和加入濃度比值求得方法回收率；取9管空白血漿各200μl平分為三組,每組3管,除不加標(biāo)準(zhǔn)系列溶液和內(nèi)標(biāo)外,經(jīng)“血漿樣品的處理方法”處理后,于殘渣中加入殘渣溶解液80μl后,分別加入低(1μg·L-1)、中(10μg·L-1)、高濃度(80μg.L-1)的Dex溶液和內(nèi)標(biāo)替米沙坦(640ng·ml-1)各10μ1,以此種處理方法測得的Dex和內(nèi)標(biāo)峰面積與空白試管中加入80μl殘渣溶解液后,再加入相應(yīng)濃度的Dex和內(nèi)標(biāo)各10μ1混勻后測得的峰面積的比值計算百分比,即得介質(zhì)效應(yīng)；分別觀察了Dex殘渣溶解液在-20℃避光放置7天和14天、低中高(50ng·L-1、500ng·L-1、4000ng·L-1)質(zhì)控血漿樣品復(fù)溶后室溫避光放置4小時、低中高質(zhì)控血漿樣品凍融1次、3次,-20℃下凍存3天和15天的穩(wěn)定性。 二、全麻肥胖患者Dex臨床藥代動力學(xué) ①受試者選擇：本試驗經(jīng)廣州軍區(qū)廣州總醫(yī)院倫理委員會批準(zhǔn),并在ClinicalTrials.gov注冊(NCT01864187)。選擇肥胖患者8名,年齡18-64歲,BMI-28kg·m-2,簽署知情同意書,于試驗前在醫(yī)院接受全面的體格檢查,對肝、腎功能進(jìn)行化驗測定,并進(jìn)行心電圖檢查,符合條件者入選。受試者無既往病史,平時很少服藥,不嗜煙酒,試驗前14天內(nèi)未用任何藥物。 ②給藥方案及血樣采集：入選8名肥胖患者,入室后連接MP30(PHILIPS公司)監(jiān)護(hù)儀監(jiān)測脈搏血樣飽和度(Sp02)、心電圖(ECG)、無創(chuàng)血壓(NBP)、呼氣末二氧化碳分壓(PETCO2)。開放外周靜脈,面罩給氧去氮,分別采用Marsh、Minto模式靜脈靶控輸注丙泊酚2-3μg·ml-1、瑞芬太尼3-4ng·m1-1,待意識消失后靜脈注射順式阿曲庫銨0.15mg·kg-1麻醉誘導(dǎo),待肌肉松弛后氣管插管,再行頸內(nèi)中心靜脈和足背動脈穿刺。經(jīng)頸內(nèi)靜脈泵入1μg·kg-1Dex10分鐘泵完。分別于注射前(Base)和注射后0、5、10、15、20、25、30、45、60、90、120、180、240、360、480分鐘于足背動脈采血5ml,采集的血樣置于肝素化的試管中,2小時內(nèi)3000r·min-1離心10分鐘,分離血漿置-20℃儲藏,15天內(nèi)采用已探出的方法進(jìn)行血藥濃度檢測。 ③血漿樣品分析：未知血漿樣品的測定按“血漿樣品的處理方法”項操作,每批建立一條標(biāo)準(zhǔn)曲線,同時分析低中高(50ng·L-1、500ng·L-1、4000ng·L-1,各兩個樣本)的質(zhì)控樣本,并以同批次的標(biāo)準(zhǔn)曲線計算各個時間點樣本中Dex和質(zhì)控樣本的濃度,根據(jù)質(zhì)控樣本的結(jié)果決定當(dāng)天數(shù)據(jù)的取舍,質(zhì)控樣本的相對偏差應(yīng)控制在±15%范圍之內(nèi)。 ④數(shù)據(jù)處理：將各受試者不同時間點樣品的血藥濃度數(shù)據(jù)列表,并計算其平均值與標(biāo)準(zhǔn)差,繪制Dex藥物濃度-時間曲線圖；然后以個體藥代動力學(xué)軟件DAS2.1.1對每個受試者的血藥濃度數(shù)據(jù)進(jìn)行處理,計算主要的藥動學(xué)參數(shù)[血藥濃度-時間曲線下面積(AUC)、血藥峰濃度(Cmax)、分布半衰期(t1/2α)、消除半衰期(tl/2β)、表觀分布容積(VI)、清除率(CLz)、平均駐留時間(MRT)],并求出參數(shù)的平均值和標(biāo)準(zhǔn)差。t1/2按t1/2=0.693/ke求得；ke是由對數(shù)血漿藥物濃度-時間曲線末端直線部分的斜率求得。 結(jié)果 一、HPLC-MS/MS測定人血漿Dex濃度 Dex在20-6000ng·L-1范圍內(nèi)線性關(guān)系良好(r2=0.9951),最低定量下限為20ng.L-1,提取回收率為82.20%-96.37%,方法回收率97.18%-103.63%,批內(nèi)精密度為3.26%-8.74%,批間精密度為8.24%-10.11%。介質(zhì)效應(yīng)百分比為99.13%-105.27%,可是為無介質(zhì)效應(yīng)影響。Dex殘渣溶解液在-20℃避光放置7天和14天、低中高(50ng·L-1、500ng·L-1、4000ng·L-1)質(zhì)控血漿樣品復(fù)溶后室溫避光放置4h、低中高質(zhì)控血漿樣品凍融1次、3次,-20℃下凍存3天和15天的穩(wěn)定性RSD均小于15%。 二、全麻肥胖患者Dex臨床藥代動力學(xué) 入組臨床8名全麻肥胖患者,采集血液Dex濃度檢測樣本共計128份。全麻肥胖患者藥代動力學(xué)過程符合二房室模型,主要的藥代動力學(xué)參數(shù)為：AUC(o-t)123.27μg·L-1-min, AUC(0-∞)138.63μg·L-1·min, t1/2α2.49min, t1/2β163.41min, V1162.96L, CLz40.20L·min-1, MRT(0-t)152.06min。 結(jié)果表明,本試驗研究出來的HPLC-MS/MS法測定人血漿中Dex已取得令人滿意的結(jié)果。首先,測定血漿中Dex及替米沙坦,每個樣品的檢測時間僅需3.0分鐘和3.6分鐘,使得樣品通過量得到實質(zhì)性的提高,有利于后期藥代動力學(xué)研究的進(jìn)行；其次MRM技術(shù)能夠同時檢測到母離子和具有特征反應(yīng)的子離子,母離子被碰撞破裂后,特定的子離子被選擇性檢測到；方法具有高度的專屬性和靈敏度,因而顯著降低了背景噪音。此外試驗中對樣品前處理為液液萃取法,該方法簡便、快捷、經(jīng)濟(jì)符合藥動學(xué)高通量的需求,而且防止了內(nèi)源性物質(zhì)在色譜柱上的殘留,延長了色譜柱使用壽命。結(jié)論 本文所建立的HPLC-MS/MS分析方法,具有專屬性強(qiáng)、靈敏度高、檢測時間快速的優(yōu)點,適用于人血漿中Dex的濃度測定,并成功應(yīng)用于藥物動力學(xué)研究。所算出的肥胖患者Dex藥代動力學(xué)參數(shù)符合二房室模型,但值得注意的是肥胖患者總體重中肌肉組織和水分比例小于同齡同性別的正常體質(zhì)量患者,但脂肪組織比例卻增大,且心排出量主要運(yùn)送至非脂肪組織[10],因此按照患者實際體重給藥,可能會導(dǎo)致藥物相對過量,造成藥物作用時間延長[11],說明用藥時必須考慮患者體重因素并相應(yīng)地減少藥物用量,以減少不良反應(yīng)和防止藥物蓄積。因此在臨床麻醉中,為了防止和避免藥物帶來的問題,肥胖患者藥物用量應(yīng)相對減少,這樣無論實際工作還是在藥品應(yīng)用經(jīng)濟(jì)學(xué)上均具有重要意義,對肥胖患者更科學(xué)更合理。肥胖患者的劑量標(biāo)準(zhǔn)應(yīng)該根據(jù)肥胖患者身體組成和血流的相應(yīng)變化來確定。
[Abstract]:Dexmedetomidine hydrochloride (Dex) chemical name: (R) -4-[1- (2,3- dimethylbenzene) ethyl]-1H- imidazole mononsalt. It was first listed in the United States in March 2000 and entered the Chinese market in 2008. As a highly selective alpha adrenaline receptor agonist, its affinity is 8 times higher than that of clonidine. Sensory neuroactivity, sedative hypnotism, anti anxiety and analgesic effect, and less adverse reactions, it has been widely used in the perioperative sedative, analgesic and other areas of [1]. on the determination of blood concentration in the drug [2-3], foreign gas chromatography tandem mass spectrometry ([4]), high effect liquid chromatography tandem mass spectrometry (High performance liquid Chr) Omatography tandem mass spectrometry, HPLC-MS/MS) [5-7], radioactivity [8] and so on. The lowest concentration of such methods is 5ng-L-1. sample pretreatment methods such as protein precipitation method [2], liquid liquid extraction [3,7] and solid-phase extraction [5], etc. based on this experiment, Agilent6410 was established and verified by liquid liquid extraction. The HPLC-MS/MS method of Dex concentration in plasma samples. Obese patients have less mass of muscle tissue per kilogram and more fat tissue. In general, the flow of blood flow into adipose tissue is less, about 5% of the cardiac output, while the flow of inflow to the viscera is 73%, and the muscle is 22%[9]. If the dosage of the drug is increased according to the overall weight, it will lead to some groups. The increase of drug concentration in the blood of the woven blood, which eventually leads to the relative excess of plasma drugs and the increase of adverse reactions. Up to now, the pharmacokinetic characteristics of Dex in general anesthesia patients have not been seen, so we will explore the HPLC-MS/MS method to detect the concentration of Dex in the plasma of obese patients with general anesthesia and clarify the Dex intravenous pump after infusion. The pharmacokinetic characteristics in obese patients provide a reference for clinical research and more rational application of Dex.
objective
First, the concentration of Dex in human plasma was determined by HPLC-MS/MS.
Two, the clinical pharmacokinetic characteristics of Dex in obese patients under general anesthesia.
First, the HPLC-MS/MS method was established to determine the concentration of Dex in human plasma:
(1) mass spectrometric analysis: under positive ion detection, Dex and internal standard telmisartan are detected by the electrospray ion source (ESI source), and the molecular ions are selected by m/z201.1 and m/z512.2., respectively. The main fragments of Dex are m /z95.1, the response value is higher, and the background noise is small. The background noise is small. Therefore, the product ions of the quantitative analysis of the multi reaction monitoring model (MRM) were selected to be used for quantitative analysis. The main product fragments produced by Telmisartan were m/z276.1, which was used as the product ion for monitoring the quantitative analysis. The QQQ conditions were explored by capillary electropressure 4000V, spray gas pressure 45psi, and the flow velocity of 10L. Min in the dry gas. -1, the temperature of the dry gas is 350 degrees centigrade.
(2) chromatographic conditions: Agilent Eclipse Plus C18 (4.6mm x 150mm, 3.5 mu m), and mobile phase of methanol: 1% formate water (75:25, V/V); flow rate of 0.5ml. Min-1; the column temperature is 35 C; the sample volume is 2 1..
(3) the treatment of plasma samples: the precise addition of 200 to 1 in the plasma sample is placed in the glass centrifuge tube of 10ml, adding 640ng / ml-1's telmisartan methanol solution 10 mu 1, and 0.2mo1 L-1 sodium hydroxide solution 100 mu 1, rapidly oscillating for 1 minutes, and then adding ethyl acetate: dichloromethane (4:1 liquid) 1ml seal, vortex oscillation 2 minutes, 2800r min-1 In the centrifuge for 10 minutes, the organic layer 800 mu 1 taper glass centrifuge tube was absorbed, and the nitrogen in the water bath was dried at 30 C. The residue dissolved (methanol: water =80:20) was added to the sample before entering the sample. The residue was dissolved in 30 seconds quickly, sucked into the 1.5ml centrifuge tube, 20000r. Min-1 was centrifuged for 5 minutes, and the supernatant was 2 mu 1.
(4) standard curve: the plasma samples with Dex concentration of 0,20,50100200500100020004000 and 6000ng. L-1 were arranged in accordance with "the treatment method of plasma samples". By HPLC-MS/MS analysis, the ratio of Dex peak area to the internal standard peak area (Y) was the longitudinal coordinate, and the ratio of Dex concentration to the internal standard concentration (X) in plasma was the transverse coordinates, and 20-6000ng. L-1 concentration was obtained. A standard curve within a degree range.
Method confirmation: including specificity, standard curve, quantitative lower limit, precision, recovery, medium effect and stability. Specific properties: at least 6 different individuals' blank biological sample chromatograms, blank biological samples and control chromatograms (marked concentration) and biological sample chromatograms after drug use should be examined by chromatography. Curve: generally, the regression analysis method (such as weighted least square method) is used to evaluate the regression equation. It is necessary to establish a standard curve with at least 6 concentrations. The quantitative range should cover the concentration range of all the biological samples to be measured, and the concentration of the unknown sample can not be calculated by the method of extrapolation from the quantitative range. The relative standard deviation (RSD) should be less than 20% within the concentration range of the drug concentration or the detection of Cmax 1/10-1/20 in the 3-5 half-life periods. The accuracy should be at the true concentration of 80%-120%, at least by the test results of 5 standard samples; precision: low (50NG. L-1), medium (500ng. L-1) and Gao Nong, respectively. The plasma quality control samples of Dex (4000ng. L-1) were divided into 15 samples, divided into 3 batches, 5 copies per batch, and simultaneously carried out with the standard curves of each batch, calculated the measured concentration of the quality control samples, compared with the preparation concentration, and obtained the precision of the method; the recovery rate: the blank plasma was treated with the "plasma sample treatment" and then added to the phase after the treatment was not added to the internal standard. The concentration of Dex and telmisartan were calculated, and the recovery rate was calculated with the ratio of peak area to two treatments per concentration. The ratio of Dex peak area and internal standard peak area was taken into the standard curve with the ratio of Dex peak area to the internal standard peak area. The ratio of the concentration and concentration ratio was calculated and the recovery rate was calculated. The 200 micron l of 9 tubes of blank plasma was divided into three groups. Each group of 3 tubes, with the exception of the standard series solution and the internal standard, after the treatment of the "plasma sample treatment", after the residue is added to the residue dissolved in 80 mu L, adding low (1 mu g. L-1), medium (10, G. L-1), high concentration (80 u g.L-1) Dex solution and internal standard rice Chatain (640ng. ML-1) each 10 mu 1, as measured by the method of Dex and internal standard. After adding 80 l residue dissolved in the peak area and blank test tube, the percentage calculated by the ratio of the ratio of the corresponding concentration of Dex and the internal standard 10 mu 1, that is, the ratio of the ratio of the ratio of the peak area, that is, the medium effect is obtained, and the plasma samples of the Dex residue dissolved in -20 C for 7 and 14 days, and the low middle height (50NG. L-1500ng. L-14000ng. L-1) plasma samples are observed. After the products were redissolved, they were stored at room temperature for 4 hours. Low, medium and high quality plasma samples were freeze-thaw 1 times, 3 times, and stored at -20 C for 3 days and 15 days.
Two, the clinical pharmacokinetics of Dex in general anesthesia patients with obesity
The subjects were selected: the test was approved by the ethics committee of Genenral Hospital of PLA Guangzhou Military Area and registered in ClinicalTrials.gov (NCT01864187). 8 obese patients, aged 18-64 years old, BMI-28kg m-2, signed informed consent, received a comprehensive physical examination in the hospital before the trial, tested the liver and kidney function, and carried out the electrocardiogram. The subjects were selected without any previous medical history. They seldom took medicine and were not addicted to alcohol and tobacco. They did not use any drugs within 14 days before the test.
(2) drug delivery scheme and blood sample collection: 8 obese patients were selected, and the pulse blood sample saturation (Sp02), electrocardiogram (ECG), non-invasive blood pressure (NBP) and end expiratory carbon dioxide partial pressure (PETCO2) were monitored by MP30 (PHILIPS) monitor after admission to the room. The external peripheral vein was open and the mask was given to oxygen to nitrogen, and the intravenous target controlled infusion of propofol was 2-3 by Marsh and Minto mode respectively. G / ml-1 and remifentanil 3-4ng m1-1 were induced by intravenous injection of CIS CIS atracurium 0.15mg. Kg-1 after the consciousness disappeared. After the muscle relaxation, the endotracheal intubation and the puncture of the internal jugular central vein and the dorsal foot artery were performed. The pump was pumped through the internal jugular vein for 1 mu g. Kg-1Dex10 minutes before injection (Base) and 0,5,10,15,20,25,30,45,60,90,12 after the injection, respectively. The blood samples collected from the dorsum of the foot were 5ml in 0180240360480 minutes. The blood samples were collected in the heparinated test tube, 3000r min-1 was centrifuged for 10 minutes in 2 hours. The separated plasma was stored at -20 C, and the blood concentration was detected by the method that had been detected within 15 days.
(3) analysis of plasma samples: the determination of the unknown plasma samples was operated according to the "treatment method of plasma samples". A standard curve was established in each batch. The quality control samples of low middle and high (50NG. L-1500ng. L-14000ng. L-1, two samples) were analyzed, and the concentration of Dex and quality control samples in each time point sample was calculated with the standard curve of the same batch. According to the result of the quality control sample, the trade-off between the date and the quality control sample should be determined. The relative deviation of the quality control sample should be within the range of + 15%.
(4) data processing: to list the blood drug concentration data of the samples at different time points of the subjects and calculate the average and standard deviation, draw the Dex drug concentration time curve, and then use the individual pharmacokinetic software DAS2.1.1 to process the blood concentration data of each subject and calculate the main pharmacokinetic parameters [blood drug concentration - time]. The area under the curve (AUC), the concentration of the blood drug peak (Cmax), the half life (t1/2 alpha), the elimination half life (tl/2 beta), the apparent distribution volume (VI), the clearance rate (CLz), the average resident time (MRT)], and the average value of the parameters and the standard deviation.T1/2 according to the t1/2= 0.693/ke; Ke is the slope of the end straight part of the logarithmic plasma drug concentration time curve. Get it.
Result
1. HPLC-MS/MS determination of Dex concentration in human plasma
Dex has a good linear relationship (r2=0.9951) in the range of 20-6000ng L-1. The lowest quantitative lower limit is 20ng.L-1, the recovery rate is 82.20%-96.37%, the recovery rate is 97.18%-103.63%, the intra batch precision is 3.26%-8.74%, the percentage of the inter batch precision is 99.13%-105.27%, but it dissolves.Dex residue for the non medium effect. The liquid was placed at -20 C for 7 days and 14 days. The plasma samples of low medium high (50NG. L-1500ng. L-14000ng. L-1) were dissolved at room temperature and placed 4H at room temperature. The low medium high quality plasma samples were frozen thawing 1 times, 3 times, and the stability of the frozen storage for 3 days and 15 days at -20 C was less than 15%..
Two, the clinical pharmacokinetics of Dex in general anesthesia patients with obesity
In the group of 8 general anesthesia patients, 128 samples of blood Dex concentration were collected. The pharmacokinetics of general anesthesia patients were in accordance with the two atrioventricular model. The main pharmacokinetic parameters were: AUC (O-T) 123.27 mu g. L-1-min, AUC (0- infinity) 138.63 u g. L-1 min, T1 /2. RT (0-t) 152.06min.
The results show that the HPLC-MS/MS method for the determination of Dex in human plasma has achieved satisfactory results. First, the determination of Dex and telmisartan in plasma is only 3 minutes and 3.6 minutes for each sample, which makes the sample increase substantially, and is beneficial to the study of pharmacokinetics in the later period; secondly, M The RM technology can simultaneously detect the mother ion and the sub ion with the characteristic reaction. After the parent ion is collided and ruptured, the specific subions are selectively detected. The method has a high specificity and sensitivity, thus significantly reducing the background noise. In addition, the sample is treated with liquid extraction in the front of the sample. The method is simple, quick, and fast. It meets the high demand of pharmacokinetics and prevents the residue of endogenous substances on the chromatographic column and prolongs the service life of the column.
The HPLC-MS/MS analysis method established in this paper has the advantages of strong specificity, high sensitivity and rapid detection time. It is suitable for the determination of Dex concentration in human plasma and successfully applied to the study of pharmacokinetics. The pharmacokinetic parameters of Dex in obese patients are in accordance with the two atrioventricular model, but it is worth noting that the total weight of the obese patients is in the median muscle. The proportion of meat tissue and water is less than that of normal body mass in the same age, but the proportion of adipose tissue increases, and the amount of cardiac output is mainly transported to the non fat tissue [10]. Therefore, the drug may lead to a relatively excessive drug in accordance with the actual weight of the patient and cause the drug.

【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R614

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本文編號：1868205