依托泊苷亚微乳在大鼠体内的药动学研究

目的研究依托泊苷亚微乳在大鼠体内的药动学特征,并与依托泊苷注射剂比较。方法大鼠随机分为4组,每组6只,分别尾iv依托泊苷亚微乳2.5、5.0、10.0 mg/kg以及依托泊苷注射剂5 mg/kg,于给药后0.033、0.167、0.333、0.667、1、1.5、2、2.5、3、3.5、4、5、6 h取血。采用HPLC法测定大鼠全血中依托泊苷。结果大鼠iv依托泊苷亚微乳2.5、5、10 mg/kg后的药动学参数分别为t1/2:0.37、0.43、0.46 h;C0:4.72、8.7、15.5 mg/L;AUC0-t:1.57、2.84、6.21 mg·h/L。大鼠尾iv依托泊苷注射剂5 mg/L后的药动学参数分别为:t1/2为0.34 h,C0为7.53 mg/L,AUC0-t为2.63 mg·h/L。依托泊苷亚微乳给药剂量在2.5~10 mg时,t1/2无显著差异,C0、AUC0-t呈剂量相关性,符合线性药动学特点。与注射剂比较,依托泊苷亚微乳的t1/2延长,AUC增大。结论依托泊苷亚微乳的生物利用度有所提高,但半衰期仍然较短。     

紫苏醇壳聚糖亚微乳在大鼠体内的药动学研究

目的:研究紫苏醇(POH)溶液(POH-SL)、POH亚微乳(POH-SE)与POH壳聚糖亚微乳(POH-CSSE)在大鼠体内的药动学特征。方法:将大鼠随机分为POH-SL组、POH-SE组及PH-CSSE组,每组6只,尾静脉注射相应药物65 mg/kg,采用高效液相色谱法检测给药后5、10、15、30、45、60、120、240、360、480、600 min的血药浓度,Kinetica 4.4.1软件计算药动学参数。色谱条件:色谱柱为Agilent Zorbax XDB C18,流动相为乙腈-水(40∶60),流速为1.0 ml/min,检测波长为210 nm,柱温为30℃,进样量为20μl。结果:POH检测质量浓度的线性范围为0.05²5μg/m(lr=0.999 6),平均方法回收率为(95.64±0.03)%25μg/m(lr=0.999 6),平均方法回收率为(95.64±0.03)%^{(98.65±0.09)}%,RSD≤8.62%(n=5)。POH-SL、POH-SE、POH-CSSE的药动学参数分别为t1/2β(81.65±0.107)、(121.58±0.021)、(130.69±0.031)min,AUC0-∞(4 944.19±0.024)、(6 716.22±0.044)、(7 008.46±0.035)mg·min/L,K10(0.005 397±0.012)、(0.004 216±0.012)、(0.004 186±0.013)min-1;其中与POH-SL比较,POH-SE和POH-CSSE的t1/2β、AUC0-∞明显增加(P<0.05)。结论:POH-CSSE在体内有较好的长循环作用,有助于延长POH的吸收。     

羟基喜树碱长循环亚微乳的制备及其在大鼠体内的药动学

以二硬脂酰磷脂酰乙醇胺-聚乙二醇(DSPE-PEG)2000共聚物、大豆磷脂S75、硬脂酰胺、泊洛沙姆188为辅料制备羟基喜树碱长循环亚微乳,所得长循环亚微乳平均粒径为(170.7±10.0)nm,ζ电位为(28.98±1.06)mV.同法制备了未PEG修饰的亚微乳.以喜树碱为内标,采用HPLC法测定血浆中的药物浓度.大鼠分别单剂量尾静脉注射给予羟基喜树碱长循环亚微乳、未PEG修饰的亚微乳和注射液.药动学研究表明,长循环亚微乳的t1/2β.和MRT均较未修饰亚微乳和注射液显著延长,提示PEG修饰的亚微乳在体内有较好的长循环作用.     

水飞蓟宾口服亚微乳剂的制备及大鼠体内药动学研究

目的:制备水飞蓟宾口服亚微乳并研究其在大鼠体内的药动学。方法:采用薄膜分散-探头超声法制备水飞蓟宾亚微乳。大鼠分别灌服水林佳(市售水飞蓟宾磷脂复合物胶囊)和水飞蓟宾亚微乳,于不同时间点取血,HPLC法测定血药浓度,采用DAS(Date Acquisition System)软件求算药动学参数。结果:水飞蓟宾亚微乳制剂的平均粒径为(155.9±2.2)nm,Zeta电位为-(29.62±0.03)mV,体外释放动力学符合Weibull方程;大鼠灌服水林佳和水飞蓟宾亚微乳后MRT分别为(1.73±0.03)h和(3.44±0.08)h,AUC0-∞分别为(1.83±0.38)mg·h·L-1和(4.72±0.48)mg·h·L-1。水飞蓟宾亚微乳的相对生物利用度为257.9%。结论:水飞蓟宾制成亚微乳制剂后延长了药物在体内的滞留时间,提高了药物的口服生物利用度。     

芒果苷自微乳给药系统的制备及其大鼠体内药动学研究

目的制备芒果苷（mangiferin,MGF）自微乳给药系统（SMEDDS）,并对其进行药动学研究。方法评价系统自微乳化速度,激光散射仪测定乳化后形成微乳粒径的大小及分布情况;以PBS6.8缓冲液为释放介质,考察MGF-SMEDDS的体外释放行为;采用HPLC法测定大鼠血浆药物浓度,考察MGF-SMEDDS的体内吸收情况。结果体系在1min内可乳化完全,乳化后粒径在20nm左右;MGF-SMEDDS在120min的累积释放率可达80%以上;大鼠体内药动学研究结果表明,MGF-SMEDDS达峰时间为0.43h,是MGF的1/7;最大血药浓度为0.93mg/L,是MGF的2.16倍。结论自微乳给药系统可以显著提高MGF的体外释放,改善其药动学性质。     

多西他赛自微乳注射液在大鼠体内药动学及组织分布

目的测定大鼠单剂量（12．55mg／kg）尾静脉注射多西他赛自微乳溶液和市售注射剂的血药浓度,比较2组的药动学行为;研究多西他赛自微乳溶液和市售注射剂在正常大鼠心,肝,脾,肺,肾中的分布情况。方法采用高效液相法测定sD大鼠给药后不同时问点的血药浓度以及组织分布情况。结果多西他赛自微乳溶液组和市售制剂组的主要药动学参数除表观分布容积VI／F外,t1/2β,CL、AUC0→∞、MRT0→∞均无显著性差异（P〉0．05）。结论自制微乳与市售制剂在大鼠体内具有相似的动力学特征,没有显著改善药物在大鼠体内的组织分布。     

紫杉醇自乳化微乳的制备及其在大鼠体内的药动学

目的:制备紫杉醇微乳,并对其急性过敏反应和大鼠体内的药动学进行考察。方法:三角相图法探讨了紫杉醇自乳化微乳(以下简称自微乳)的形成条件,采用均匀设计优化组成制备自微乳。以紫杉醇注射液对照,比较自微乳豚鼠的急性过敏反应和大鼠体内的药动学。结果: 以三辛酸甘油酯三丁酸甘油酯(1 ∶1)为油相,无水乙醇作助乳化剂制备的紫杉醇自微乳经生理盐水稀释后形成稳定的微乳,平均粒径为(16±s3)nm。以紫杉醇注射液作对照,自微乳豚鼠的急性过敏反应明显降低。统计矩分析,紫杉醇自微乳与紫杉醇注射液大鼠体内平均滞留时间分别为3. 89h和2. 52h,自微乳延长药物在大鼠体内的滞留时间。结论:通过优化处方制备的紫杉醇自微乳具有较好的稳定性,并可显著降低急性过敏反应。     

多西他赛亚微乳注射液在犬体内的药动学

目的研究多西他赛(DTX)亚微乳注射液在比格犬体内的药动学,比较亚微乳注射液与普通注射液犬体内药动学差异。方法采用单剂量双周期自身交叉设计,Beagle犬前肢分别静脉滴注(20 mg.m-2)DTX亚微乳注射液和DTX注射液(泰素帝),分别于0、0.33、0.67、1、1.5、2、2.5、3、4、6、8、12、24 h采血,血浆中DTX采用液相色谱-质谱联用(LC-MS)法测定。结果相同剂量的DTX亚微乳或普通注射液的AUC0-24分别为(476.80±96.18)和(451.94±43.91)μg.h.L-1,Cmax分别为(510.06±168.58)和(466.71±73.14)μg.L-1,t1/2分别为(5.76±4.24)和(4.40±0.51)h,2种制剂的各药动学参数无显著性差异(P>0.05)。结论多西他赛制成亚微乳制剂后,两者具有相似的体内药动学行为。亚微乳制剂DTX的药-时曲线下面积和峰浓度有所增加,消除半衰期延长可能与制剂形式不同有关。     

地西泮亚微乳注射液处方及制备工艺的研究

目的：确定地西泮亚微乳注射液的制备处方及工艺。方法：采用二级高压均质法制备地西泮亚微乳注射液，分别考察了高压均质条件，油相组成，乳化剂及稳定剂用量，pH调节，灭菌过程对制剂稳定性的影响。结果：采用15％油相（MCT与LCT等比例混合），1．2％豆磷脂，0．06％油酸钠，2．5％甘油，均质前调节至pH8．0，以20℃，80MPa压力均质6-10次，所制备的地西泮亚微乳注射液在4-25℃下12个月内理化性质没有明显变化。结论：本品具有良好的物理化学稳定性。     

青蒿琥酯自微乳在大鼠体内的药动学研究

目的 建立大鼠血浆中青蒿琥酯的HPLC-MS/MS测定方法,并研究青蒿琥酯自微乳在大鼠体内的药动学特征。方法 12只SD大鼠随机分为2组,单剂量分别灌胃（50 mg·kg^-1）青蒿琥酯自微乳和青蒿琥酯原料药,以格列吡嗪为内标,用LC-MS/MS测定给药后血浆中的药物浓度,并计算药动学参数。结果 青蒿琥酯血浆样品的线性范围为1.0~1 000.0 ng·mL^-1,回归方程为A=294.74C-439.33（r=0.999 6）,定量下限为1.0 ng·mL^-1。日内、日间变异系数（RSD）均<10%,符合生物样品的分析要求。青蒿琥酯原料药和青蒿琥酯自微乳的药动学参数C_max、t_1/2和AUC_0→t分别为：（87.6±8.80）ng·mL^-1,（1.88±0.33）h和（43.3±1.74）h·ng·mL^-1;（421±41.6）ng·mL^-1,（1.48±0.17）h和（282±17.7）h·ng·mL^-1。其中,C_max和AUC_0→t存在显著性差异（p<0.01）。结论 该方法简便灵敏,可用于血浆中青蒿琥酯的含量测定,经灌胃给药后,与原料药比较,青蒿琥酯自微乳能显著提高生物利用度。     

磷酸川芎嗪乳剂在大鼠体内的药动学及组织分布研究

目的： 通过研究磷酸川芎嗪乳剂在大鼠体内的药动学和组织分布，探究磷酸川芎嗪乳剂的生物利用度和脑靶向性。方法： 大鼠静脉注射50 mg·kg^-1磷酸川芎嗪制剂，给药后，在不同时间采血，最后切除大鼠心脏，肝脏，脾脏，肺，肾，和脑。所有样品均采用液相色谱-质谱/质谱联用法（HPLC/MS/MS）进行检测，用DAS 2.1.1软件使用非房室分析计算药动学参数。结果： 与参比制剂（磷酸川芎嗪注射液）相比，乳剂制剂血浆中的药动学参数无显著差异。在血浆中，乳剂的AUC_0-∞和C_max分别为（4 406.96±977.08）mg·L^-1·min和（52.131±13.61）mg·L^-1。组织分布研究发现磷酸川芎嗪乳剂较参比制剂在脑组织分布更多。结论： 磷酸川芎嗪乳剂在心、肝、脾、肺、肾中有靶向趋势，比参比制剂更易分布在组织中。磷酸川芎嗪乳剂制剂具有脑靶向性。     

Side-Effect Evaluation of a New Diazepam Formulation: Venous Sequela Reduction Following Intravenous (iv) Injection of a Diazepam Emulsion in Rabbits

Diazepam has been incorporated into a stable, submicronized injectable emulsion. Venous sequela induction in rabbits following iv administration of diazepam in a marketed hydroalcoholic solution and in the emulsion were determined and compared over a 5-day period. There was a marked difference in the local reactions induced by the iv administration of the marketed diazepam hydroalcoholic solution and the diazepam emulsion, even on the first postinjection day. This difference was confirmed by pathological analysis. The highest mean venous sequela score was reached by the rabbit group injected with the marketed diazepam solution. It should be noted that no statistical difference was observed between the saline and the diazepam emulsion rabbit groups during the 5 days of the observation period. The moderate increase in the venous sequela score values compared to that for the saline solution should be attributed to the intrinsic effect produced by diazepam itself, and not to the emulsion vehicle, which was shown not to induce any vascular reaction in the present study.     

Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects

Six healthy subjects between the ages of 21 and 31 years received diazepam tablets orally at a dose of 5 mg t.i.d. atO, 5, and 10hr on days 1–13. On day 14, the dose was 5 mg at 0 and 5 hr and 15 mg at 10 hr. Subsequently, the dose was 15 mg once daily on days 15–24. Numerous plasma samples were obtained during the multiple-dose regimen, and appropriate equations were fitted to all the multiple-dose data. Diazepam absorption was satisfactorily described by a first-order process, with disposition characterized by a linear two-compartment open model. The harmonic mean absorption half-life was 32 min, and the harmonic mean terminal exponential half-life was 57hr. The mean apparent oral total drug plasma clearance was 22.7ml/hr/kg. Steady-state plasma levels of the primary metabolite, desmethyldiazepam, were reached after 5–8 days of dosing. Steady-state diazepam plasma concentration-time profiles suggested that once daily administration of the total daily dose at bedtime might be a satisfactory dosing regimen.     

Pharmacokinetics and anticonvulsant effects of diazepam in children with severe falciparum malaria and convulsions

AIMS: Convulsions are a common complication of severe malaria in children and are associated with poor outcome. Diazepam is used to terminate convulsions but its pharmacokinetics and pharmacodynamics have not been studied in this group. Accordingly, we carried out a comparative study of the pharmacokinetics of intravenous (i.v.) and rectal (p.r.) diazepam. METHODS: Twenty-five children with severe malaria and a convulsion lasting >5 min were studied. Sixteen children received diazepam intravenously (i.v.; 0.3 mg kg(-1)) and nine rectally (p.r.; 0.5 mg kg(-1)). Plasma diazepam concentrations were measured by reversed phase high-performance liquid chromatography. The duration of convulsions, depth of coma, respiratory and cardiovascular parameters were monitored. RESULTS: Median maximum plasma diazepam concentrations of 634 (range 402-1507) ng ml(-1) and 423 (range 112-1953) ng ml(-1) were achieved at 5 and 25 min following i.v. and p.r. administration, respectively. All patients except three (one i.v. and two p.r.) achieved plasma diazepam concentration >200 ng ml(-1) within 5 min. Following p.r. administration, plasma diazepam concentrations were more variable than i.v. administration. A single dose of i.v. diazepam terminated convulsions in all children but in only 6/9 after p.r. administration. However, nine children treated with i.v. and all those treated with p.r. diazepam had a recurrence of convulsions occurring at median plasma diazepam concentrations of 157 (range: 67-169) and 172 (range: 74-393) ng ml(-1) , respectively. All the children in the i.v. and four in the PR diazepam group who had recurrence of convulsions required treatment. None of the children developed respiratory depression or hypotension. CONCLUSIONS: Administration of diazepam i.v. or p.r. resulted in achievement of therapeutic concentrations of diazepam rapidly, without significant cardio-respiratory adverse effects. However, following p.r. administration, diazepam did not terminate all convulsions and plasma drug concentrations were more variable.     

甲状腺功能对地西泮及其代谢产物在大鼠体内代谢的影响

目的：研究甲状腺功能对地西泮及其代谢物的药代动力学影响。方法：采用HPLC技术，测定不同甲状腺功能状态时，大鼠血液中地西泮及其体内主要代谢产物去甲基地西泮的浓度。结果：甲亢组大鼠地西泮在体内消除加速，峰浓度下降，AUC减少，消除T1/2缩短。甲减组大鼠则消除减慢，峰浓度增高，AUC增大，消除孔。延长。而其主要代谢产物去甲地西泮的药动学参数则相反。结论：甲状腺功能提高时，大鼠对地西泮的代谢能力明显增加，消除加速；而甲腺功能降低则相反。     

克拉霉素脂肪乳剂在大鼠体内药动学和组织分布研究

目的研究克拉霉素脂肪乳剂在大鼠体内药动学和组织中的分布情况,并与克拉霉素注射液相比。方法通过高压均质方法制备克拉霉素脂肪乳剂,通过微生物管碟法测定克拉霉素在大鼠体内血药浓度和组织中药物浓度。结果克拉霉素脂肪乳剂和克拉霉素注射液药-时曲线相似并均符合二室模型,两种剂型的AUC0-t分别为(66.76±16.34)和(59.00±11.20)μg·h/ml。大鼠单剂量静脉注射37.5mg/kg克拉霉素脂肪乳剂和溶液剂后,测定各时间点各组织中药物浓度,以肺为最高。与溶液剂相比,脂肪乳剂提高了脾、肺、肝、肾和脑的药物分布。结论克拉霉素脂肪乳剂与克拉霉素溶液剂血药浓度相似,但脂肪乳剂明显改变了克拉霉素体内组织分布,说明更有助于治疗局部脏器感染。     

Relationship between cerebral pharmacokinetics and anxiolytic activity of diazepam and its active metabolites after a single intra-peritoneal administration of diazepam in mice

The relationship between the cerebral pharmacokinetics of diazepam and its active metabolites (desmethyldiazepam, oxazepam) and the anxiolytic effect evaluated by the four-plates test and the light/dark test were investigated after a single intra-peritoneal injection of diazepam (1 mg/kg or 1.5 mg/kg). For up to 30 min after administration, the sedative effect interfered with the anxiolytic effect, thus the results of the anxiolytic effect were not interpretable. From 30 min to 60 min after administration, this interference disappeared, the cerebral level of benzodiazepines was stable (the brain elimination of diazepam was compensated for by the appearance of desmethyldiazepam followed by oxazepam) but the anxiolytic effect decreased dramatically in all the tests with diazepam 1 mg/kg or 1.5 mg/kg. The acute tolerance to benzodiazepines and the difference of affinity for subtypes of GABA(A) receptors between diazepam, desmethyldiazepam, oxazepam could explain this result.     

Clearance of diazepam can be impaired by its major metabolite desmethyldiazepam

Summary The pharmacokinetics of a single intravenous dose of diazepam 0.1 mg/kg was studied in 6 healthy volunteers, in random order under controlled conditions and following pretreatment with its major metabolite, desmethyldiazepam (20 mg/day) for one week. In the two subjects with the highest plasma concentration of desmethyldiazepam (990 and 1100 ng/ml, respectively), total plasma clearance (Cl) of diazepam was reduced after desmethyldiazepam, by 31% and 54%, respectively. In three individuals there was a moderate decrease of 14% to 21%, and no effect was seen in one volunteer. Cl was significantly reduced (11.5±1.8 vs. 9.1±3.3 ml/min;p=0.015) and elimination half-life tended to be prolonged (38.5±10.4 vs. 65.8±67.1 h;p=0.15). It is concluded that high concentrations of desmethyldiazepam can influence the elimination of its parent drug diazepam by product inhibition.