紫杉醇糖被复脂质体的制备及其在小鼠体内的组织分布

用HPLC法测定小鼠单剂量（10mg／kg）尾静脉注射自制紫杉醇糖被复脂质体或市售紫杉醇注射剂后的心、肝、脾、肺、肾和血浆的药物浓度。结果表明，糖被复脂质体组紫杉醇主要被肺摄取，在肺部的滞留时间明显延长，肺中AUC为注射剂的9．6倍；并减少了肝、脾组织的蓄积量。说明此紫杉醇糖被复脂质体在小鼠体内的分布优于注射液，有明显的肺靶向性。     

紫杉醇纳米混悬剂在大鼠体内的药动学和小鼠的组织分布

目的:考察紫杉醇纳米混悬剂在大鼠体内的药动学及小鼠体内的组织分布情况。方法:将紫杉醇注射液和紫杉醇纳米混悬剂2种制剂静脉给药后,采用HPLC法分别测定给药后5,10,15,30min及1,2,4,6,8,12h时大鼠的血药浓度,给药后5,15,30min及1,2,4,8,12h时紫杉醇在小鼠心、肝、脾、肺、肾、脑组织中的含量,对2种制剂的体内生物分布特征和靶向性进行评价。结果:大鼠血浆中,紫杉醇纳米混悬剂和紫杉醇注射液的消除相半衰期分别为(5.6±0.7)和(3.8±0.4)h;AUC分别为(5.2±0.4)和(20.3±1.1)mg.h.L-1;MRT分别为(3.2±0.4)和(2.8±0.3)h;Cl分别为(2.05±0.22)和(0.56±0.19)L.kg-1.h-1。与紫杉醇注射液相比,紫杉醇纳米混悬剂在肝、脾、脑组织中的药物含量显著增加。结论:相对于市售紫杉醇注射液,紫杉醇纳米混悬剂向靶部位富集,显著降低了非靶器官的药物浓度,可减轻制剂不良反应,使药物在血浆中的循环时间延长。     

紫杉醇胶束与紫杉醇注射剂在荷瘤裸鼠体内的组织分布

目的评价紫杉醇胶束与注射剂在荷瘤裸鼠体内组织分布特征,为胶束制剂的临床应用提供参考依据。方法将Balb/c雄性荷瘤小鼠前肢腋皮下接种人结肠癌HT29细胞,待瘤体长到100 mm3左右后,分别经尾静脉注射给予紫杉醇胶束(PTX-PM)和紫杉醇注射剂(PTXI)均20 mg.kg-1,每3 d一次,共给药7次。于最后一次给药后30、60、180、360 min时处死裸鼠取血和各主要组织器官(心、肝、肠、肾、胃、肺、脾等),用HPLC法测定组织中紫杉醇的药物浓度。结果 2种制剂经静脉注射后,在各个时间点对各组织的药物分布趋势相似,以浓度高低依次为肝、肠、肾、胃、脾、肺、心等;PTX-PM组的紫杉醇在主要器官组织的浓度明显低于PTXI组(P<0.01或P<0.05)。其中PTX-PM组的紫杉醇在血浆中的浓度显著低于PIXI组(P<0.01),而30 min时PTX-PM组的紫杉醇在肝脏的浓度却高于PTXI组(P<0.01)。在各个时间点PTX-PM组的紫杉醇在主要器官组织的浓度与血浆浓度的比值明显高于PTXI组(P<0.01)。结论紫杉醇胶束有助于减少紫杉醇对血液系统的毒性,避免紫杉醇注射剂中聚氧乙烯蓖麻油引起的过敏反应,具有良好的临床应用前景。     

丹皮酚对小鼠体内药动学及组织分布情况的研究

目的探讨丹皮酚在小鼠体内的药动学及组织分布情况。方法采用HPLC法测定丹皮酚在血浆、组织中含量。结果小鼠一次性灌胃丹皮酚（65mg·kg^-1）后。体内药动学呈单室模型,其主要分布在肝,其次是脾、小肠上端、肾、结肠、心、肺。结论本研究为设计丹皮酚新型给药系统提供可靠的生物药剂学依据。     

SN-38脂质体的药动学及组织分布学特征

目的研究SN-38脂质体大鼠体内药动学及小鼠组织分布学特征,为进一步非临床研究提供一定的实验基础。方法以盐酸伊立替康注射液(irinotecan,简称CPT-11)为参比制剂,大鼠尾静脉单次给予不同剂量的SN-38脂质体,于不同时间点眼框取血;小鼠尾静脉给予单剂量的SN-38脂质体,于2 h处死,取心、肝、脾、肺、肾等组织匀浆。并且建立HPLC法,用于大鼠血浆及小鼠组织样品中SN-38的含量测定。结果低、中、高3种剂量的SN-38脂质体在大鼠体内均消除较快,其t1/2无明显差异,AUC则随剂量的增加而增加。小鼠尾静脉注射SN-38脂质体后,主要聚集在肝、脾、肺中,且其在心、肾组织中的含量低于对照组。结论 SN-38脂质体在大鼠体内呈线性动力学消除。小鼠组织分布结果表明其对于肝、脾等网状内皮细胞丰富的组织靶向性强,能够提高该器官的治疗指数;同时还可降低对心、肾组织的毒性及不良反应。     

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。     

盐酸二甲双胍在小鼠体内的药动学和组织分布

目的:研究盐酸二甲双胍在小鼠体内的药动学和组织分布。方法:小鼠灌胃给予盐酸二甲双胍200mg·kg-1,并在给药后0、0.33、0.67、1、2、3、4、6、8、10h共10个时间点采集血样和小肠、肾、肝、胃、肌肉、肺、脾、心脏组织样品(每个时间点小鼠3只),采用高效液相色谱法测定并计算血浆和各组织样品中二甲双胍的浓度。用DAS2.0软件计算药动学参数。结果:盐酸二甲双胍在小鼠体内的血药浓度-时间曲线符合二室模型;主要药动学参数AUC为(52.93±2.34)mg·h·L-1,CL为(0.059±0.002)L·h-1,t1/2为(3.61±0.22)h,tmax为0.67h,Cmax为(18.61±0.78)mg·L-1。在给药后0.67h,所有的组织中都能检测到二甲双胍;给药后10h,心、肝、脾、肺中已检测不到二甲双胍。各组织的AUC值从大到小排列依次为小肠、肾、胃、肝、肌肉、肺、心、脾。结论:盐酸二甲双胍进入小鼠体内后吸收及清除都较迅速,且在小鼠体内分布广泛,但在各组织分布情况显著不同。     

高通量分析紫杉醇在动物体内的药动学及组织分布

目的 建立基于96孔板的高通量测定SD大鼠血浆和荷瘤小鼠组织中紫杉醇浓度的方法.方法 将SD大鼠血浆样品、荷瘤小鼠组织样品及内标物多西他赛置于96孔板中,采用96/384道半自动液体移液器取液进行高通量的液液萃取,高效液相色谱-串联质谱（LC/MS/MS）法测定各生物样品的紫杉醇浓度.结果 紫杉醇的线性范围为2 ～ 500 μg/L,最低定量下限为2μg/L.在SD大鼠血浆中,紫杉醇的半衰期、平均滞留时间、药时曲线下面积、药时曲线下总面积、药物清除率、表观分布容积分别为（6.3 ±0.4）h、（7.16 ±0.13）h、（3 070 ±201）（h· μg）/L、（3246±199）（h· μg）/L、（1.55±0.09）L/（h·kg）、（13±8）L/kg.荷瘤小鼠尾静脉注射紫杉醇注射液7.5 mg/kg后0.5、1、2、4、8h,紫杉醇在小鼠心、肝、脾、肺、肾、肿瘤中含量差异有统计学意义（P＜0.05）.结论 LC/MS/MS法专一、准确、稳定、简便并且实现了高通量分析,适用于紫杉醇的SD大鼠药动学和荷瘤小鼠组织分布研究.     

载长春西汀聚乙二醇-聚乳酸纳米粒在小鼠体内的药动学及组织分布

目的探讨载长春西汀聚乙二醇-聚乳酸纳米粒(Vin纳米粒)在小鼠体内的药动学及组织分布。方法 48只ICR小鼠随机平均分成两组,每组分别尾静脉注射长春西汀注射液(Vin注射液)和Vin纳米粒,给药剂量均为5 mg·kg-1,于给药后不同时间摘眼球取血并制备各组织样品,采用蛋白沉淀法提取药物。建立液相色谱-串联质谱联用(LC-MS/MS)分析方法测定血浆及各组织Vin浓度,用DAS 2.0药动学软件计算药动学参数。以重量-平均总靶向系数(TE*)和AUQ0-t为指标评价纳米粒的组织分布及靶向性。结果小鼠血浆中Vin纳米粒的AUC0-t是Vin注射液的165.4倍;t1/2由0.47 h延长到2.71 h,增加5.76倍;MRT0-t增加4.58倍。Vin纳米粒在脑中的滞留时间为注射液的2.24倍,t1/2为注射液的3.97倍,AUC0-t增加1.62倍。静脉注射Vin纳米粒后,对肝和脾靶向明显;在血浆、心、肝、脾、肺、肾和脑组织中,Vin纳米粒的AUQ0-t均大于Vin注射液的AUQ0-t,Vin纳米粒的总AUQ0-t是Vin注射液的65.58倍。结论 Vin纳米粒可延长在体内的循环时间,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。     

Intravenous Hydrophobic Drug Delivery: A Porous Particle Formulation of Paclitaxel (AI-850)

No HeadingPurpose. To develop a rapidly dissolving porous particle formulation of paclitaxel without Cremophor EL that is appropriate for quick intravenous administration.Methods. A rapidly dissolving porous particle formulation of paclitaxel (AI-850) was created using spray drying. AI-850 was compared to Taxol following intravenous administration in a rat pharmacokinetic study, a rat tissue distribution study, and a human xenograft mammary tumor (MDA-MB-435) model in nude mice.Results. The volume of distribution and clearance for paclitaxel following intravenous bolus administration of AI-850 were 7-fold and 4-fold greater, respectively, than following intravenous bolus administration of Taxol. There were no significant differences between AI-850 and Taxol in tissue concentrations and tissue area under the curve (AUC) for the tissues examined. Nude mice implanted with mammary tumors showed improved tolerance of AI-850, enabling higher administrable does of paclitaxel, which resulted in improved efficacy as compared to Taxol administered at its maximum tolerated dose (MTD).Conclusions. The pharmacokinetic data indicate that paclitaxel in AI-850 has more rapid partitioning from the bloodstream into the tissue compartments than paclitaxel in Taxol. AI-850, administered as an intravenous injection, has been shown to have improved tolerance in rats and mice and improved efficacy in a tumor model in mice when compared to Taxol.     

Pharmacokinetics of paclitaxel-containing liposomes in rats

In animal models, liposomal formulations of paclitaxel possess lower toxicity and equal antitumor efficacy compared with the clinical formulation, Taxol. The goal of this study was to determine the formulation dependence of paclitaxel pharmacokinetics in rats, in order to test the hypothesis that altered biodistribution of paclitaxel modifies the exposure of critical normal tissues. Paclitaxel was administered intravenously in either multilamellar (MLV) liposomes composed of phosphatidylglycerol/phosphatidylcholine (L-pac) or in the Cremophor EL/ethanol vehicle used for the Taxol formulation (Cre-pac). The dose was 40 mg/kg, and the infusion time was 8 to 9 minutes. Animals were killed at various times, and pharmacokinetic parameters were determined from the blood and tissue distribution of paclitaxel. The area under the concentration vs time curve (AUC) for blood was similar for the 2 formulations (L-pac: 38.1±3.32 μg-h/mL; Cre-pac: 34.5±0.994 μg-h/mL), however, the AUC for various tissues was formulation-dependent. For bone marrow, skin, kidney, brain, adipose, and muscle tissue, the AUC was statistically higher for Cre-pac. For spleen, a tissue of the reticuloendothelial system that is important in the clearance of liposomes, the AUC was statistically higher for L-pac. Apparent tissue partition coefficients (K_p) also were calculated. For bone marrow, a tissue in which paclitaxel exerts significant toxicity, K_p was 5-fold greater for paclitaxel in Cre-pac. The data are consistent with paclitaxel release from circulating liposomes, but with efflux delayed sufficiently to retain drug to a greater extent in the central (blood) compartment and reduce penetration into peripheral tissues. These effects may contribute to the reduced toxicity of liposomal formulations of paclitaxel.     

Pharmacokinetics, tissue distribution and anti-tumour efficacy of paclitaxel delivered by polyvinylpyrrolidone solid dispersion

Objectives Paclitaxel is a potent anti‐cancer drug that has exhibited clinical activity against several tumours. Unfortunately, serious side effects are associated with Taxol, the commercial formulation of paclitaxel, which contains Cremophor EL (CrEL). Currently, the main focus of developing paclitaxel formulations is on improving efficacy and reducing toxicity. A novel, Cremophor‐free, paclitaxel solid dispersion (PSD) was prepared in our laboratory previously. The primary aim of this study was to evaluate the pharmacokinetics, tissue distribution, acute toxicity and anti‐tumour efficacy of the PSD compared with Taxol. Methods SD rats were used to examine the pharmacokinetics and tissue distribution of PSD. The acute toxicity of PSD was evaluated in ICR mouse. The anti‐tumor activity of PSD was assessed in an in vivo anti‐tumor nude mice model inoculated with human SKOV‐3 cancer cells. Key findings The two formulations presented different pharmacokinetic behaviour. The plasma AUC of paclitaxel in the PSD was 5.84‐fold lower than that of Taxol, and the mean residence time, total body clearance and apparent volume of distribution of paclitaxel in the PSD were increased by 1.73, 4.67 and 8.57 fold, respectively. However, the two formulations showed similar tissue distribution properties. CrEL, the vehicle in Taxol, decreased the clearance of paclitaxel from plasma. The LD50 (median lethal dose) was 34.8 mg/kg for Taxol, whereas no death was observed at 160 mg/kg for the PSD. The anti‐tumour activity of PSD was similar to that of Taxol at a dose of 15 mg/kg. Most importantly, the improved tolerance of PSD enabled a higher administrable dose of paclitaxel, which resulted in improved efficacy compared with Taxol administered at its maximum tolerated dose. Conclusions These results suggest that the PSD, a CrEL‐free formulation, is a promising approach to increase the safety and efficacy of paclitaxel.     

Enhanced oral bioavailability of paclitaxel by D-alpha-tocopheryl polyethylene glycol 400 succinate in mice

Paclitaxel is widely used to treat several types of solid tumors. The commercially available paclitaxel formulation contains Cremophor/ethanol as solubilizers. This study evaluated the effects of D-alpha-tocopheryl polyethylene glycol 400 succinate (TPGS 400) on the oral absorption of paclitaxel in mice. Mice were given an intravenous (18mg/kg) or oral (100mg/kg) dose of paclitaxel solubilized in Cremophor/ethanol or in TPGS 400/ethanol formulations. Paclitaxel plasma concentrations and pharmacokinetic parameters were determined. The maximal plasma concentrations of paclitaxel after an oral dose were 1.77+/-0.17 and 3.39+/-0.49microg/ml for Cremophor/ethanol and TPGS 400/ethanol formulations, respectively, with a similar time at 40-47min to reach the maximal plasma concentrations. The oral bioavailability of paclitaxel in TPGS 400/ethanol (7.8%) was 3-fold higher than that in Cremophor/ethanol (2.5%). On the other hand, the plasma pharmacokinetic profiles of intravenous paclitaxel demonstrated a superimposition for the two formulations. Furthermore, TPGS 400 concentration-dependently increased the intracellular retention of Rhodamine 123 in Caco-2 cells and enhanced paclitaxel permeability in monolayer Caco-2 cultures. TPGS 400 at concentrations up to 1mM did not inhibit testosterone 6beta-hydroxylase, a cytochrome P450 isozyme 3A in liver microsomes metabolizing paclitaxel. Our results indicated that TPGS 400 enhances the oral bioavailability of paclitaxel in mice and the enhancement may result from an increase in intestinal absorption of paclitaxel.     

紫杉醇白蛋白纳米粒抗肿瘤临床研究进展

以白蛋白为载体的紫杉醇纳米粒在抗肿瘤方面发挥了重要作用。本文对紫杉醇白蛋白纳米粒体内药动学过程、纳米粒转运机制进行探讨,并就近几年来紫杉醇白蛋白纳米粒在乳腺癌、非小细胞肺癌及其他恶性肿瘤方面的临床研究作一综述,为临床应用提供借鉴。     

Preparation and evaluation of Cremophor-free paclitaxel solid dispersion by a supercritical antisolvent process

Objectives To avoid the major adverse effects induced by Cremophor EL formulated in the commercial paclitaxel products of Taxol. Methods An injectable paclitaxel solid dispersion free of Cremophor was prepared by a supercritical antisolvent process and then was fully characterized and investigated with regard to its short‐term and long‐term stability. Pharmacokinetics in rats was also evaluated compared with the commercial product. Key findings The solid dispersion system at a 1/20/40 weight ratio of paclitaxel/HP‐β‐CD/HCO‐40 had a paclitaxel solubility of about 10 mg/ml, an almost 10 000‐fold increase over its aqueous solubility. This system was physically stable for at least six months or four weeks in accelerated conditions (40 ± 2°C; RH: 75 ± 5%) and stress conditions (60°C), respectively. The precipitation time of paclitaxel solid dispersion in 0.9% sodium chloride injection at a concentration of 1000 µg/ml was above 70 h at room temperature. Intravenous administration of paclitaxel solid dispersion at a dose of 6 mg/kg revealed no significant differences when compared with the commercial product. However, our results obtained at a dose of 12 mg/kg showed a striking non‐linear increase in the plasma Cmax and AUCall with increased dose. In addition, the concentrations of paclitaxel in various organs in the solid dispersion group were found to be higher than those of Taxol at 6 mg/kg, and the paclitaxel levels in these organs increased proportionately with increasing dose. Conclusions Nano‐scale paclitaxel solid dispersion without Cremophor EL provided advantageous results over Taxol with respect to the physicochemical properties, safety, clinic convenience and pharmacokinetic behaviour in rats.     

Effect of unpurified Cremophor EL on the solution stability of paclitaxel

Taxol for Injection Concentrate contains a solution of paclitaxel in a 50:50 v/v mixture of Cremophor EL (cleaned):ethanol. Cleaned, rather than unpurified, Cremophor EL is used as a cosolvent because paclitaxel was observed to be less stable in the presence of unpurified Cremophor. In order to understand the cause of this paclitaxel instability, various studies were performed. The results of these studies, coupled with the examination of degradation products, suggested that carboxylate anions present in the unpurified Cremophor catalyze the degradation of paclitaxel by general base catalyzed ethanolysis. Stabilization of Taxol for Injection Concentrate prepared with unpurified Cremophor can be achieved by addition of strong acids, resulting in neutralization of the carboxylate anions. Separately, a quality control test for the cleaning procedure of Cremophor is needed to insure stability of Taxol for Injection Concentrate. A colorimetric indicator test was identified which can distinguish between good and poor quality cleaned Cremophor as it pertains to paclitaxel stability.     

Cremophor EL pharmacokinetics in a phase I study of paclitaxel (Taxol) and carboplatin in non-small cell lung cancer patients

The purpose of our study was to investigate the pharmacokinetics of Cremophor EL following administration of escalating doses of Taxol (paclitaxel dissolved in Cremophor EL/ethanol) to non-small cell lung cancer (NSCLC) patients. Patients with NSCLC stage IIIb or IV without prior chemotherapy treatment were eligible for treatment with paclitaxel and carboplatin in a dose-finding phase I study. The starting dose of paclitaxel was 100 mg/m2 and doses were escalated with steps of 25 mg/m2, which is equal to a starting dose of Cremophor EL of 8.3 ml/m2 with dose increments of 2.1 ml/m2. Carboplatin dosages were 300, 350 or 400 mg/m2. Pharmacokinetic sampling was performed during the first and the second course, and the samples were analyzed using a validated high-performance liquid chromatographic assay. A total of 39 patients were included in this pharmacokinetic part of the study. The doses of paclitaxel were escalated up to 250 mg/m2 (20.8 ml/m2 Cremophor EL). Pharmacokinetic analyses revealed a low elimination-rate of Cremophor EL (CI=37.8-134 ml/h/m2; t 1/2=34.4-61.5 h) and a volume of distribution similar to the volume of the central blood compartment (Vss=4.96-7.85 l). In addition, a dose-independent clearance of Cremophor EL was found indicating linear kinetics. Dose adjustment using the body surface area, however, resulted in a non-linear increase in systemic exposure. The use of body surface area in calculations of Cremophor EL should therefore be re-evaluated.     

Measurement of fraction unbound paclitaxel in human plasma.

The clinical pharmacokinetic behavior of paclitaxel (Taxol) is distinctly nonlinear, with disproportional increases in systemic exposure with an increase in dose. We have recently shown that Cremophor EL, the formulation vehicle used for i.v. administration of paclitaxel, alters drug distribution as a result of micellar entrapment of paclitaxel, and we speculated that the free drug fraction (fu) is dependent on dose and time-varying concentrations of Cremophor EL in the central plasma compartment. To test this hypothesis, a reproducible equilibrium dialysis method has been developed for the measurement of paclitaxel fu in plasma. Equilibrium dialysis was performed at 37 degrees C in a humidified atmosphere of 5% CO(2) using 2.0-ml polypropylene test tubes. Experiments were carried out with 260-microliter aliquots of plasma containing a tracer amount of [G-(3)H]paclitaxel with high-specific activity against an equal volume of 0.01 M phosphate buffer (pH 7.4). Drug concentrations were measured by both reversed-phase HPLC and liquid scintillation counting. Using this method, fu has been measured in three patients receiving three consecutive 3-weekly courses of paclitaxel at dose levels of 135, 175, and 225 mg/m(2) and found to range between 0.036 and 0.079. The method was also used to define concentration-time profiles of unbound drug, estimated from the product of the total plasma concentration and fu.