阿霉素脂质体犬肝动脉栓塞后的体内分布与药代动力学研究

用阿霉素脂质体与碘油混合后对大经导管肝动脉栓塞，用反相高效液相色谱法研究了阿霉素在犬体内的分布及药代动力学。结果显示，阿霉素脂质体－碘油栓塞组大血浆阿霉素浓度显著低于阿霉素灌注组（P＜0.01）和阿霉素－碘油栓塞组（P＜0．05），而其血浆阿霉素消除半衰期和肝组织中阿霉素浓度与后两组相比则显著增加（p＜0．01及p＜0．05）。说明阿霉素脂质体与碘油混合肝动脉栓塞后可显著提高阿霉素对肝脏的靶向性，延长阿霉素消除半衰期．     

脂蟾毒配基PLGA-TPGS纳米粒在小鼠体内肝的靶向性

目的：研究脂蟾毒配基（Resibufogenin,RBG）/香豆素-6（Coumarin-6,C6）乙交酯丙交酯共聚物-维生素E聚乙二醇1000琥珀酸酯（PLGA-TPGS）纳米粒（RBG/C6-loaded PLGA-TPGS nanoparticles,RCPTN）在小鼠体内的分布及对小鼠肝脏的靶向性。方法：建立RP-HPLC法测定RBG在小鼠血浆及肝、心、脾、肺和肾等生物样品中的浓度,将RCPTN和RBG溶液（RS）经小鼠尾静脉注射后,测定不同给药时间后小鼠血浆及各脏器中的RBG浓度。采用靶向指数（TI）、选择性指数（SI）、相对靶向效率（Re）和靶向效率（Te）4个指标,同时通过对各器官进行冰冻切片,荧光倒置显微镜下观察荧光纳米粒RCPTN在各器官的分布,定性、定量的全面评价RCPTN对肝脏的靶向性。结果：除SI_血浆在0.08,0.5 h时,TI和SI的数值均大于1,表明RCPTN在各时间点对肝脏的靶向作用良好;在血浆、肝、心、脾、肺、肾中的Re分别为2.1、40.1、1.1、16.4、11.7、1.4,即在整个考察时间范围内,RCPTN在肝脏中的药时曲线下面积（AUC）是RS的40.1倍,表明载药纳米粒能将药物更好的传递至肝脏;RCPTN在血浆、心、脾、肺、肾中的Te均大于3,表明RBG在肝脏比血浆和其他脏器匀浆中的AUC高达3倍以上,且在心脏中的Te（28.1）是RS在心脏中Te（0.8）的35.1倍,表明RCPTN具有良好的肝脏靶向作用,且可显著降低RBG在心脏中的分布。冰冻切片图可见在1 h的RCPTN组小鼠各器官中,肝中荧光分布面积最大,其次是脾和肺,最后是肾和心。表明RCPTN静脉注射后对肝脏有良好的靶向性,这与用TI、SI、Re和Te 4个靶向指标评价RCPTN对肝脏的靶向性结果是一致的。结论：RCPTN对小鼠肝脏有良好的靶向作用,在心脏分布较少。     

间接门静脉与直接门静脉灌注5-氟尿嘧啶的药动学比较

目的：研究经兔脾动脉、肠系膜上动脉（即间接门静脉）灌注5－Fu和直接门静脉灌注5－Fu的药动学变化，以证实临床经间接门静脉灌注化疗药物治疗肝肿瘤的合理性。方法：3组家兔分别经脾动脉（SA组）、肠系膜上动脉（SMA组）和门静脉（PV组）灌注5－Fu，用高产液相色谱仪检测不同时间门静脉血中的药物浓度。结果：PV组AUC明显高于SA组和SMA组（P＜0．01），SA组又高于SMA组（P＜0．05）；PV组T1／2明显低于SA、SMA组（P＜0．01），SA组又低于SMA组（P＜0．05）；30min后3组门静脉血中的5－Fu浓度趋向于一致。结论：经间接门静脉灌注可作为直接门静脉灌注的一个补充手段应用于肝肿瘤的“双灌注”治疗。     

阿霉素脂质体犬肝动脉栓塞后的体内分布与药代动力学研究

用阿霉素脂质体与碘油混合后对犬经导管肝动脉栓塞，用反相高效液相色谱法研究了阿霉素在犬体内的分布及药代动力学。结果显示，阿霉素脂质体－碘油栓塞组犬血浆阿霉素浓度显著低于阿霉素灌注组（ｐ〈０．０１）和阿霉素－碘油栓塞组（ｐ〈０．０１），而其血浆阿霉素消除半衰期和肝组织中阿霉素浓度与后两组相比则显著增加（ｐ〈０．０１及ｐ〈０．０５）。说明阿霉素脂质体与碘油混合肝动脉栓塞后可显著提高阿霉素对肝脏的靶向性，     

氟尿嘧啶白及微球对原发性肝癌患者肝动脉栓塞后体内药动学

目的：研究肝癌患者Fu白及微球肝动脉栓塞后体内药动学过程。方法：11例肝癌患者随机分成两组,一组为微球栓塞组,另一组以常规Fu注射液作肝动脉化疗为对照组。血中Fu浓度采用反相高效液相色谱法,所得血药浓度数据用3P87药动学程序处理。结果：Fu白及微球体内过程符合二室模型,Fu血峰浓度（Cmax)低,仅为对照组的20％（P＜0．01）,曲线下面积（AUC）和表观分布容积（Vc)明显增大,大分布衰期（T1／2α）和消除半衰期（T1／2β）明显延长,分别为对照组的3．7倍和93．8倍（P＜0．01）。清除率（CL)减低。结论：Fu白及微球在体内能缓释Fu,起到长效,高效,低毒的作用,显示较好的临床应用前景。     

槐定碱纳米脂质体在大鼠体内药代动力学及组织分布研究

目的:研究槐定碱纳米脂质体静脉给药后在大鼠体内药代动力学及组织分布。方法:大鼠尾静脉注射给药后,采用HPLC法测定血浆药物浓度,比较盐酸槐定碱注射液、槐定碱纳米脂质体的药代动力学;另HPLC法测定各组大鼠心脏、肝、脾、肺、肾中4 h内的槐定碱浓度,分析药物组织分布情况。结果:槐定碱纳米脂质体的大鼠药时曲线AUC是普通注射液的2.42倍,体内滞留时间延长;各组织中槐定碱浓度均在0.5 h达最高后开始降低;与槐定碱注射液比较,静脉注射槐定碱纳米脂质体后4 h内的平均浓度在肝、脾中均升高,在其他组织中的浓度均降低。结论:槐定碱纳米脂质体能提高药物在肝、脾中的分布,具有肝、脾靶向性,尤其是肝靶向性。     

胃动素在大腹皮促动力效应中的变化及其意义

目的：探讨大腹皮的促胃肠动力作用机制。方法：16只Wistar大鼠随机分为大腹皮组及对照组,给大鼠灌服大腹皮水提液1h后,放射免疫分析法测定血浆及胃肠组织匀浆中胃动素（MTL）的含量,免疫组化法观察胃窦及空腹中MTL的分布变化。结果：灌服大腹皮煎液后,大鼠血浆及胃肠组织匀浆中MTL的含量显著升高（P＜0．01或＜0．05）,胃窦及空肠MTL阳性物质的表达明显增加（P＜0．01或＜0．05）。结论：大腹皮的促胃肠动力作用与血浆、胃肠和组织匀浆中MTL水平的增加及胃肠道MTL细胞分布变化有密切关系。     

替加氟磁性长循环脂质体在大鼠体内的药代动力学和靶向性

目的研究替加氟磁性长循环脂质体经肝动脉给药的药代动力学和组织靶向性。方法采用高效液相色谱仪检测大鼠生物样品中替加氟的浓度。结果磁控并加热的替加氟磁性长循环脂质体组的肝内8h药时曲线下面积(AUC)是游离替加氟组的17.4倍,是替加氟长循环脂质体组的3.9倍;其肝外组织血浆和肾的AUC比游离替加氟组低。其肝靶向效率达到73.9%。结论替加氟磁性长循环脂质体经肝动脉给药能显著增加药物的肝脏靶向性,可能降低其肾毒性。     

大黄素固体脂质纳米粒在小鼠体内的组织分布研究

目的:研究大黄素(EMO)固体脂质纳米粒(SLN)在小鼠体内的组织分布情况和肝靶向性。方法:72只小鼠分为2组,分别尾ivEMO-SLN混悬液和EMO溶液,在给药0.083、0.250、0.500、1.000、2.000、6.000h时分别取样,以高效液相色谱法测定不同时间点血浆、心、肝、脾、肺、肾中EMO的浓度,计算EMO-SLN对EMO的药物总靶向效率摄取率(re)、总靶向性(Te)。结果:肝中所得r和Te值均为最高。结论:EMO-SLN具有较高的肝靶向性,且强于EMO。     

氯沙坦和哌唑嗪调节早期高血压大鼠体内降钙素基因相关肽反应的差异

目的：探讨高血压早期大鼠体内降钙素基因相关肽（CGRP）的变化,并观测两类降压药物,氯沙坦或哌唑嗪在降压过程中对CGRP的反应差异。方法：采用经典的两肾一夹型高血压大鼠（Goldblatt,2K1C）为研究模型,夹尾法测定大鼠清醒状态下血压,通过公式计算出平均动脉压;放射免疫法血浆内CGRP和血管紧张素Ⅱ（AngⅡ）的含量。反转录聚合连反应（RT-PCR）测定脊髓背根神经节中CGRP mRNA的表达。结果：收缩压、平均动脉压在结扎肾动脉10d后较对照组快速升高（P〈0．01）,给予氯沙坦或哌唑嗪治疗5d后,血压明显降低（P〈0．01）;实验末,高血压未治疗组血浆中AngⅡ、CGRP浓度（P〈0．01,P〈O．01）和脊髓背根神经节中的CGRP mRNA的表达明显升高（P〈0．05）,高血压氯沙坦治疗组可进一步升高大鼠血浆中AngⅡ、CGRP浓度（P〈0．01,P〈0．01）和脊髓背根神经节中的CGRP mRNA的表达（P〈0．05）;但在高血压哌唑嗪治疗组大鼠血浆中AngⅡ变化不显著（P〉0．05）,但CGRP浓度和脊髓背根神经节中的CGRP mRNA的表达与未治疗组相比显著降低（P〈0．05,P〈0．01）。结论：在肾血管性高血压早期含CGRP感觉神经功能存在代偿性增高,氯沙坦或哌唑嗪的不同降压机制也可能与其影响体内CGRP合成和释放差异有关。     

Differential retention of doxorubicin in the organs of two strains of rats

Fluorescence microscopy and high pressure liquid chromatography were used to study the decrease of doxorubicin (DXR) concentrations in the liver, spleen, heart, lung, kidney and skeletal muscle of two strains of rats at various times after a single intravenous injection of the drug (8 mg kg-1). DXR was located within the cell nucleus and was mostly undegraded, it persisted, especially in heart, lungs and spleen where it was detectable 10 days after injection. The DXR/DNA ratio, was used as an index of nuclear fixation of the drug. A major difference in the DXR/DNA ratio between the two strains were observed in heart and spleen results; the DXR/DNA ratio was significantly higher in heart and spleen compared with lung, liver and kidney in both strains.     

Pharmacokinetics of doxorubicin incorporated in solid lipid nanospheres (SLN).

The pharmacokinetics of doxorubicin incorporated as ion-pair into solid lipid nanospheres (SLN) was compared with that of the commercial solution of the drug. Male albino rats (Wistar-derived strain) were treated i.v. with equivalent doses (6 mg kg(-1)) of two different doxorubicin formulations: an aqueous dispersion of SLN carrying doxorubicin and a commercial doxorubicin solution (Adriablastina). These formulations were injected, under general anaesthesia, through a cannula into the jugular vein and blood samples were collected at 1, 15, 30, 45, 60, 120 and 180 min after administration. After 180 min rats were killed and samples of liver, heart, lung, kidney, spleen and brain were collected. Blood and tissue samples were analysed by a spectrofluorimetric method. The anthracycline concentration in the blood was markedly higher at each point times with the SLN than with the commercial solution. The drug concentration was also higher in the lung, spleen and brain. SLN-treated rats showed a lower doxorubicin concentration in liver, heart and kidney. The results showed that SLN increased the area under the curve (0-180 min) of doxorubicin compared to conventional doxorubicin solution and led to a different body distribution profile.     

Intravenous Administration to Rabbits of Non-stealth and Stealth Doxorubicin-loaded Solid Lipid Nanoparticles at Increasing Concentrations of Stealth Agent: Pharmacokinetics and Distribution of Doxorubicin in Brain and Other Tissues

The pharmacokinetics and tissue distribution of doxorubicin incorporated in non-stealth solid lipid nanoparticles (SLN) and in stealth solid lipid nanoparticles (SSLN) (three formulations at increasing concentrations of stearic acid-PEG 2000 as stealth agent) after intravenous administration to conscious rabbits have been studied. The control was the commercial doxorubicin solution. The experiments lasted 6 h and blood samples were collected at fixed times after the injections. In all samples, the concentration of doxorubicin and doxorubicinol were determined. Doxorubicin AUC increased as a function of the amount of stealth agent present in the SLN. Doxorubicin was still present in the blood 6 h after the injection of SLN or SSLN, while no doxorubicin was detectable after the i.v. injection of doxorubicin solution. Tissue distribution of doxorubicin was determined 30 min, 2 and 6 h after the administration of the five formulations. Doxorubicin was present in the brain only after the SLN administration. The increase in the stealth agent affected the doxorubicin transported into the brain; 6 h after injection, doxorubicin was detectable in the brain only with the SSLN at the highest amount of stealth agent. In the other rabbit tissues (liver, lungs, spleeen, heart and kidneys) the amount of doxorubicin present was always lower after the injection of any of the four types of SLN than after the commercial solution. In particular, all SLN formulations significantly decreased heart and liver concentrations of doxorubicin.     

Intravenous administration to rabbits of non-stealth and stealth doxorubicin-loaded solid lipid nanoparticles at increasing concentrations of stealth agent: pharmacokinetics and distribution of doxorubicin in brain and other tissues

The pharmacokinetics and tissue distribution of doxorubicin incorporated in non-stealth solid lipid nanoparticles (SLN) and in stealth solid lipid nanoparticles (SSLN) (three formulations at increasing concentrations of stearic acid-PEG 2000 as stealth agent) after intravenous administration to conscious rabbits have been studied. The control was the commercial doxorubicin solution. The experiments lasted 6 h and blood samples were collected at fixed times after the injections. In all samples, the concentration of doxorubicin and doxorubicinol were determined. Doxorubicin AUC increased as a function of the amount of stealth agent present in the SLN. Doxorubicin was still present in the blood 6 h after the injection of SLN or SSLN, while no doxorubicin was detectable after the i.v. injection of doxorubicin solution. Tissue distribution of doxorubicin was determined 30 min, 2 and 6 h after the administration of the five formulations. Doxorubicin was present in the brain only after the SLN administration. The increase in the stealth agent affected the doxorubicin transported into the brain; 6 h after injection, doxorubicin was detectable in the brain only with the SSLN at the highest amount of stealth agent. In the other rabbit tissues (liver, lungs, spleeen, heart and kidneys) the amount of doxorubicin present was always lower after the injection of any of the four types of SLN than after the commercial solution. In particular, all SLN formulations significantly decreased heart and liver concentrations of doxorubicin.     

Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats.

Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin were prepared as drug delivery systems. The pharmacokinetics and tissue distribution of doxorubicin in these SLN were studied after i.v. administration to conscious rats and were compared to the commercial solution of doxorubicin. The same dose of each formulation (6 mg kg(-1)of body weight) of doxorubicin was injected in the rat jugular vein. Blood samples were collected after 1, 15, 30, 45, 60 min and 2, 3, 6, 12, and 24 h after the injection. Rats were sacrificed after intervals of 30 min, 4 h, and 24 h and samples of liver, spleen, heart, lung, kidney, and brain were collected. In all samples, the concentration of doxorubicin and of the metabolite, doxorubicinol, were determined. Doxorubicin and doxorubicinol were still present in the blood 24 h after injection of stealth and non-stealth SLN, while they were not detectable after the injection of the commercial solution. The results confirmed the prolonged circulation time of the SLN compared to the doxorubicin solution. In all rat tissues, except the brain, the amount of doxorubicin was always lower after the injection of the two types of SLN than after the injection of the commercial solution. In particular, SLN significantly decreased the heart concentration of doxorubicin.     

波棱瓜子提取物在大鼠体内分布的初步研究

目的:初步了解波棱瓜子提取物在大鼠体内的组织分布情况,为进一步确定其药效成分及作用机制奠定基础。方法:大鼠单次灌胃给予一定剂量的波棱瓜子乙酸乙酯提取部位,分别在给药后1 h、2 h处死并解剖大鼠,取心、肝、脾、肺、肾、脑六个组织;采用高效液相色谱法(HPLC)对比空白组织、给药组织及体外样品,对各组织中移行成分进行确定,了解波棱瓜子提取物中各成分在大鼠体内的分布状态。结果:大鼠给药后,肺出现了4个移行成分,心、肝组织中出现了两个移行成分,脾、肾组织在2 h出现了一个移行成分,脑组织中未有移行成分出现。结论:波棱瓜子提取物口服给药后,多种成分均有吸收。给药后1 h~2 h间,各脏器分布广泛,其中在肺脏中原型成分积蓄最多,肝脏中出现代谢成分,且药物进入肝、肺脏的速度较快;心、脾、肾中原型成分的积蓄较小,脑组织中未出现任何移行成分,该药似不能通过血脑屏障。     

两种丹酚酸注射剂在小鼠体内组织分布的研究

目的：注射用丹参多酚酸盐和注射用丹参多酚酸是临床常用的两种丹酚酸类注射剂,两者主要成分均为丹酚酸B,本文以丹酚酸B为检测指标,初步探究两种注射剂在小鼠体内的组织分布情况。方法：雄性ICR小鼠随机（数字表法）分为A组（注射用丹参多酚酸盐组）、B组（注射用丹参多酚酸组）,剂量均为250 mg·kg^-1（以丹酚酸B含量计）,两组每次随机（数字表法）取5只小鼠于尾静脉注射,1,5,10,15,30,60 min后摘眼球取血并颈椎脱臼处死,迅速分离心、肝、脾、肺、肾、脑组织,采用高效液相色谱（HPLC）法测定血清及各组织中丹酚酸B的含量。结果：给药1 min时,B组肝、脾、肾组织的丹酚酸B含量显著高于A组（P<0.05）;给药10 min时,B组小鼠心、脾、肺、脑组织中丹酚酸B的浓度显著高于A组（P<0.05）;给药15 min时,B组小鼠心、肝、脾、肺、肾组织中丹酚酸B的浓度均显著高于A组（P<0.05）;给药30 min时,B组小鼠肝、脾、肺、肾、脑组织中丹酚酸B的浓度均显著高于A组（P<0.05）;给药期间,B组脑组织中丹酚酸B的含量均高于A组,且5,10,30 min时有显著差异（P<0.05）。结论：本实验初步研究了两种丹酚酸注射剂在小鼠体内的组织分布规律,注射用丹参多酚酸的脑药浓度高于注射用丹参多酚酸盐,可能与其制剂中所含甘露醇开放血脑屏障作用有关。     

磺胺嘧啶铈乳膏经大鼠阴道和皮肤给药后体内铈离子分布研究

目的:研究磺胺嘧啶铈乳膏经大鼠阴道和皮肤给药后器官组织中铈离子的分布情况。方法:取大鼠随机分为实验组及正常对照组,每组9只,实验组经大鼠阴道给予磺胺嘧啶铈乳膏0.036 g/kg,连续给药6 d;另取大鼠随机分为实验组及正常对照组,每组9只,实验组大鼠皮肤烫伤创面涂抹磺胺嘧啶铈乳膏0.036 g/kg,连续给药6 d。采用火焰原子吸收法测定各组大鼠末次给药后8、24、72 h时心、肝、脾、肺、肾、子宫、阴道黏膜/皮肤中的铈含量。结果:与正常对照组比较,实验组大鼠给药8 h时各器官组织均检出铈,分别为(0.013±0.006)^{(0.137±0.039)}μg/g,24 h时仅肾、脾、子宫、阴道黏膜/皮肤中检出铈,分别为(0.012±0.011)(0.137±0.039)μg/g,24 h时仅肾、脾、子宫、阴道黏膜/皮肤中检出铈,分别为(0.012±0.011)^{(0.085±0.037)}μg/g,72 h时各组织器官均未检出铈。结论:磺胺嘧啶铈乳膏经阴道和皮肤给药后均能进入血液循环,主要分布于阴道/皮肤、脾、肾、子宫中,但很快被代谢,不会长期蓄积。     

MDMA在急性染毒大鼠死后体内的再分布

目的:探索死后MDMA再分布变化规律及温度对死后MDMA再分布的影响。方法:将急性染毒大鼠处死后,分别置于室温下(17℃)或冷藏(4℃)。并于死后0 h2、h、24 h、48 h采集心血、外周血及心肌、肝、脾、肺组织,用液-液萃取衍生化法和气相色谱-氮磷检测器(GC-NPD)检测MDMA含量。结果:大鼠死后48 h内,随死亡时间延长,室温下心血MDMA浓度呈升高趋势(P<0.05),肝MDMA浓度先升后降(P<0.05),心肌MDMA浓度无显著性变化(P>0.05)。在死后2-24 h内,脾MDMA浓度升高(P<0.05),肺MDMA浓度下降(P<0.05)。冷藏下血液中MDMA变化幅度较小(P<0.01);组织MDMA浓度在室温和冷藏下比较差异无显著性(P>0.05)。结论:MDMA在大鼠体内存在死后再分布现象,死后血药浓度在低温下较高温下稳定。     

PEG化脂质体多柔比星在动物体内的药动学及组织分布

比较研究了PEG化脂质体多柔比星(阿霉素)受试制剂与进口同类参比制剂静注后,在动物体内的药动学及组织分布.采用HPLC法测定Beagle犬的血药浓度和荷瘤(Walker256)Wistar大鼠各组织药物浓度.结果显示,Beagle犬静注1 mg/kg受试制剂及参比制剂后,药动学参数分别为t1/2β23.0和23.5 h,表观分布容积0.060和0.062 L/kg,AUC0-∞500.29和531.57μg·ml-1h,多柔比星在犬体内的药代动力学过程均符合二室模型的特征.荷瘤(Walker256)Wistar大鼠静注5 mg/kg受试制剂及参比制剂后,脾中含量最高,其次为肿瘤、小肠、肝,皮肤中含量最低.统计学分析显示,两制剂在犬体内主要药动学参数及大鼠组织肝、心、脾、肾、小肠、皮肤和肿瘤内的分布,无显著性差异(P>0.05).