雾化吸入羟基喜树碱在兔体内分布及肺器官中药代动力学研究

目的　研究雾化吸入羟基喜树碱在兔体内分布及肺器官中药物动力学特点。方法　采用HPLC法测定不同时间点兔血浆和肺组织中羟基喜树碱浓度 ,分析雾化吸入给药后的组织分布特点 ,并对雾化吸入给药后的肺器官中药物浓度数据进行了药物动力学分析。结果　雾化吸入给药后肺组织中的药物含量最高 ,而血浆和其它组织中的含量极低。HCPT在肺组织内浓度随着时间的延长而逐渐降低 ,其药代动力学规律可用二室模型来描述。结论　雾化吸入羟基喜树碱能维持肺中的高浓度 ,其药物动力学规律与血浆药物动力学规律有所不同     

雾化吸入羟基喜树碱在小鼠体内的药代动力学研究

目的:研究雾化吸入羟基喜树碱(HCPT)在小鼠体内和肺中以及其他脏器中的药代 动力学特征.方法:采用HPLC法测定不同时间点小鼠血浆和肺组织以及其他脏器组织中羟基喜树碱的内酯和盐型的浓度,并对雾化吸入给药后的血浆和各个脏器组织中的药物浓度数据进行药代动力学分析.结果:雾化吸入给药后,肺组织中的浓度远远高于血浆和其他器官组织,血浆和其他器官组织中药物浓度较低,并且在肺组织中,内酯型比例较高.结论:雾化吸入羟基喜树碱在肺癌中能达到靶器官中的高浓度和血浆中的低浓度,两者的药物动力学规律有所不同.     

雾化吸入氨茶碱在犬体内的组织分布

目的：研究雾化吸入氨茶碱在犬体内的组织分布特点。方法：建立了采用HPLC法测定犬血清和组织中茶碱浓度的方法。比较雾化吸入和静脉滴注给药后的组织分布特点与血药浓度。结果：相对于静脉滴注途径,采用雾化吸入途径给予同剂量氨茶碱后0．25和0．5h气管组织中的药物浓度显著升高（0．25h,P〈0．01;0．5h,P〈0．05）,而药物在其他组织中的分布几乎都显著降低。雾化吸入给药后的绝对生物利用度为24．52％。结论：雾化吸入给予氨茶碱能够在维持气管和支气管药物高浓度的同时显著降低药物在其他正常组织以及血清中的分布。氨茶碱改用雾化吸入途径给药治疗哮喘和阻塞性肺疾病具有明显的优势。     

雾化吸入羟基喜树碱在肺癌小鼠体内药动学和组织分布

目的:研究雾化吸入羟基喜树碱(HCPT)后,主要活性形式内酯型(L-HCPT)和弱活性形式羧酸盐型(C-HCPT)2种不同结构在肺癌小鼠体内的药动学与组织发布。方法:建立HPLC-FLD法测定小鼠血浆及组织中L型及C型HCPT的药物浓度。分析雾化吸入给药后血浆与肺脏、心脏、肝脏、肾脏中药动学参数,并对雾化吸入给药后血浆与组织中的L/C平衡参数进行比较。结果:HCPT的线性关系良好,日内和日间精密度、回收率均符合生物样品的分析要求。雾化吸入HCPT,血浆和各个脏器中均有C-HCPT转换为L-HCPT,肺组织中HCPT显著大于血浆和其他组织。结论:雾化吸入给药具有一定的靶向性,可提高肺组织中L型药物浓度,更有利于肺癌的治疗。     

羟基喜树碱纳米粒在大鼠体内的药动学、组织分布及靶向性研究

目的:研究羟基喜树碱纳米粒在大鼠体内的药动学及组织分布特征,并探讨其靶向性。方法:将雄性SD大鼠随机分为两组,每组6只,分别单剂量尾静脉注射羟基喜树碱纳米粒和市售羟喜树碱注射液(4 mg/kg,以羟基喜树碱计),在给药后5、30、60、120、240、360、480、600、720 min时于眼底静脉丛取血500μL,采用高效液相色谱法测定不同时间点血浆中羟基喜树碱的含量,以DAS 3.0等软件计算药动学参数。另取雄性SD大鼠随机分为两组,每组24只,分别单剂量尾静脉注射羟基喜树碱纳米粒和市售羟喜树碱注射液(0.6 mg/kg,以羟基喜树碱计),在给药后30、60、120、240 min时于腹主动脉取血并摘取心、肝、脾、肺、肾、脑,采用高效液相色谱法测定不同时间点血浆及组织中羟基喜树碱的含量,考察其分布特征及靶向性。结果:羟基喜树碱纳米粒和市售羟喜树碱注射液在大鼠体内均符合二室模型,羟基喜树碱纳米粒的AUC0-720 min和AUC0-∞分别为市售羟喜树碱注射液的1.89和1.87倍,MRT0-720 min和MRT0-∞为2.74和3.00倍,t1/2β为2.75倍,组间比较差异均有统计学意义(P<0.05);给药后30 min时,羟基喜树碱纳米粒和注射液在肺中浓度最高;随着时间的推移,药物逐渐向肝部位积累,在60 min时肝药浓度达到最高。羟基喜树碱纳米粒在肝的相对摄取率最大(6.28);以肝为靶向器官,其在心、脾、肺、肾、脑和血浆中的靶向效率均大于羟喜树碱注射液;给药后30~120 min,羟基喜树碱纳米粒在心、肺(除给药后30 min外)、肾、脑、血浆中的选择性指数均显著高于羟喜树碱注射液(P<0.05或P<0.01)。结论:羟基喜树碱纳米粒延长了药物的半衰期、提高了其血药浓度、延长了其体内作用时间,且肝靶向性显著。     

雾化吸入干扰素α1b在兔体内的分布及代谢途径

目的 研究雾化吸入与肌内注射干扰素α1b(IFNα1b)在兔体内分布及代谢的差异,考察雾化吸入干扰素治疗肺部疾病的优越性. 方法 将干扰素α1b进行125I标记,选用新西兰大耳白兔,以肌内注射为对照,采用雾化吸入的方式给药,不同时间点取血,γ计数仪测定血药浓度,通过小动物活体成像系统和γ计数仪检测肺组织不同部位的药物分布情况和主要代谢脏器肝和肾中的药物含量. 结果 与肌内注射比较,雾化吸入给药后肺组织中的干扰素含量更高,肺组织内滞留时间长,血药浓度达峰时间为8 h,明显延迟,而肾组织中的药物含量始终维持较低浓度. 结论 与常规肌内注射给药相比,雾化吸入干扰素α1b肺组织药物含量高,药物体内循环时间长,是干扰素治疗肺部疾病更为有效的给药途径.     

羟基喜树碱注射液两种给药方式在小鼠体内的药代动力学研究

目的：研究10-羟基喜树碱注射液在小鼠体内的药劝学特征。方法：建立测定小鼠血浆中10-羟基喜树碱内酯形式的HPLC-荧光捡测法，小鼠尾静脉注射和腹腔注射后不同时间点进行眼眶静脉丛取血，测定血浆中内酯形式的血药浓度，并用PKBP—N1药动学程序对血药浓度进行处理。结果：10-羟基喜树碱内酯形式可与血浆中的其它成分较好地分离，在1．25-2500mg&#183;ml^-1的血药浓度范围内呈良好的线性关系。10-羟基喜树碱两种给药方式在小鼠体内的药动学特征基本相似。结论：与静脉注射给药方式比较，腹腔注射可以提高局部组织的药物浓度，减轻药物对全身的副作用.     

5-Fu雾化吸入病人血与相关组织中的药物浓度

为观察５－Ｆｕ雾化吸入在肺癌病人血及癌组织及其周围组织中的浓度,对１０例中心型肺癌病人（取组织及血标本者各５例）给予１２５％５－Ｆｕ４０ｍｌ雾化吸入,并在给药后适时取样检测血及相关组织中的５－Ｆｕ浓度,并与静脉滴注给药者做配对对照。雾化吸入即刻至给药后６小时血清中均可检测到５－Ｆｕ,但以给药即刻最高为（４５９±１７７）ｍｇ／Ｌ,显著低于静脉滴入组。术后３小时大气通、肺及肺门淋巴结内的浓度雾化吸入组均高于静脉滴入组;在肿瘤组织内浓度两组接近。     

静脉、腹腔给予羟喜树碱冻干粉针和脂质体在小鼠血液中的分布

目的 研究羟喜树碱(HCPT)冻干粉针及脂质体通过小鼠腹腔及静脉给药其血液中的分布.方法 昆明种小鼠108只随机分成4组:2组腹腔给予冻干粉针及脂质体；另2组静脉给药.给药后15,60,120 min取血,测定羟喜树碱浓度.结果 腹腔给药后在15,60 min的血药浓度,羟基喜树碱脂质体较注射用羟基喜树碱明显减少；而120 min较注射用羟基喜树碱明显增加(P＜0.05).静脉给药后在60,120 min的药物浓度,较15 min时2组均明显减少(P＜0.05)；而120 min时的药物浓度,脂质体较注射剂明显增加(P＜0.05).结论 静脉、腹腔给予冻干粉针及脂质体HCPT,药物在血液中迅速分布,很快被消除,符合其药动学特征.     

利福平聚乳酸-羟基乙酸共聚物纳米粒雾化吸入给药肺靶向性研究

目的研究利福平聚乳酸-羟基乙酸共聚物纳米粒雾化吸入给药的肺靶向性。方法分别将利福平聚乳酸-羟基乙酸共聚物纳米粒混悬液(RFP-PLGA-NPs)和利福平注射液(RFP-Sol)以雾化吸入方式给予SD大鼠,在不同时间点测定利福平在大鼠肺组织中的浓度,计算相应药动学参数,比较2种制剂在肺组织中药动学过程,并评价靶向性。结果 RFP-Sol和RFP-PLGA-NPs的Tmax分别为(1.50±0.01)h和(2.00±0.08)h,Cmax分别为(0.83±0.07)mg.L 1和(5.02±0.05)mg.L 1,AUC0→∞分别为(6.24±0.24)mg.h.L 1和(35.80±6.34)mg.h.L 1,CL分别为(4.801±0.18)L.h 1.kg 1和(0.85±0.15)L.h 1.kg 1。通过对re和Ce等靶向性指标进行分析,RFP-PLGA-NPs在肺组织中的re和Ce均>1。结论与RFP-Sol相比,RFP-PLGA-NPs经雾化吸入给药后,明显提高了肺组织中药物的分布并且延缓消除,有显著的缓释性,从而降低药物对全身的不良反应,提高对肺结核的治疗作用。     

聚乙二醇修饰的羟基喜树碱纳米脂质载体的制备及其小鼠组织分布

本研究采用熔融乳化-高压均质法制备了聚乙二醇(PEG)修饰的羟基喜树碱(HCPT)纳米脂质载体(HCPT-PEG-NLC)及非修饰的羟基喜树碱纳米脂质载体(HCPT-NLC)，并考察了其形态、粒径及包封率。测定了HCPT注射液、HCPT-PEG-NLC及HCPT-NLC 3种制剂经小鼠尾静脉注射后在血浆、心、肝、脾、肺、肾及卵巢等主要组织的浓度，评价了HCPT-PEG-NLC及HCPT-NLC在各组织的靶向性效果。透射电镜下观察，HCPT-PEG-NLC及HCPT-NLC呈球形；测得平均粒径分别为(88.6±22.5)和(127.2±43.4)nm；包封率分别为(90.51±3.29)%和(84.37±2.81)%。经小鼠尾静脉注射后，HCPT-PEG-NLC及HCPT-NLC在多数取样时间点的血药浓度较HCPT注射液有所提高，HCPT在各组织中的消除半衰期明显延长。HCPT-NLC蓄集于网状内皮系统(RES)，在肝、脾的相对摄取率(R_e)和峰浓度比(C_e)明显高于HCPT-PEG-NLC。HCPT-PEG-NLC延长了药物在血浆中的滞留时间，提高了生物利用度，MRT及AUC_{0-24 h}分别为注射液的19.80和17.02倍，并且与HCPT-NLC比较显著降低了RES的吞噬作用，在肺部表现出明显的靶向作用(R_e及C_e分别为14.51，41.35)。综上，HCPT-PEG-NLC可延长HCPT的体内循环时间，呈现明显的肺靶向性，有望作为HCPT肺癌治疗的理想载体。     

A physiologically based pharmacokinetic model for (-)-quinuclidinyl benzylate using nonlinear irreversible tissue binding parameters in rats.

The disposition characteristics of (-)-quinuclidinyl benzylate (QNB) were investigated in rats, and a physiologically based pharmacokinetic model was established using its linear and nonlinear tissue binding parameters. The steady-state distribution volume (Vdss) and systemic clearance (CLtot) were comparable after iv administration of 325 ng/kg and 3.2 mg/kg, suggesting that QNB pharmacokinetics based on plasma concentrations is linear. However, tissue accumulation was observed in the heart, lung, muscle, and brain. This accumulation persisted for over 12 hr after the iv administration of 325 ng/kg [3H]QNB. Tissue binding parameters were determined after continuous infusion of QNB. Irreversible and nonlinear binding parameters were obtained in various regions of the brain and other tissues. Reversible equilibrium concentration ratios between tissue and plasma were determined after high-dose infusion. QNB concentrations in the plasma, heart, lung, muscle, and brain were predicted after the administration of 325 ng/kg or 3.2 mg/kg. There was reasonable agreement between the model predictions and the observed data.     

Physiological disposition of aerosolized MK-679 in rats.

[14C]MK-679, a potent antagonist of leukotriene D4, was suspended in freon under pressure and sprayed into rat lungs through a tracheal cannula. The particle size of the drug was 1 to 5 microns, and the mean dose was 98.8 +/- 4.46 micrograms/rat. Time course studies indicate that MK-679 was slowly but efficiently absorbed from the lung, with only 6% of the dose remaining in the lung at 6 hr. Biliary excretion, the major route of elimination of aerosolized MK-679, accounted for 48% of the dose in 6 hr. Concentrations of the parent drug plateaued in plasma at 1 to 4 hr, and drug was not detectable in plasma at 6 hr. The parent drug accounted for 94% of the radioactivity in the lung, indicating no significant metabolism by lung tissue. The concentration of MK-679 after aerosol administration was higher in the lung and lower in plasma than after iv administration of the drug at 28 times the aerosol dose. The results of this study suggest that inhalation of MK-679 should be a considered route of administration for the treatment of asthma.     

Pharmacokinetics and tissue distribution of idarubicin-loaded solid lipid nanoparticles after duodenal administration to rats

Idarubicin-loaded solid lipid nanoparticles (IDA-SLN) and idarubicin in solution were prepared and the two formulations were administered to rats, either by the duodenal route or intravenously (iv). The aim of this research was to study whether the bioavailability of idarubicin can be improved by administering IDA-SLN duodenally to rats. Idarubicin and its main metabolite idarubicinol were determined in plasma and tissues by reversed-phase high-performance liquid chromatography. The pharmacokinetic parameters of idarubicin found after duodenal administration of the two formulations were different: area under the curve of concentration versus time (AUC) and elimination half-life were approximately 21 times and 30 times, respectively, higher after IDA-SLN administration than after the solution administration. Tissue distribution also differed: idarubicin and idarubicinol concentrations were lower in heart, lung, spleen, and kidneys after IDA-SLN administration than after solution administration. The drug and its metabolite were detected in the brain only after IDA-SLN administration, indicating that SLN were able to pass the blood-brain barrier. After iv IDA-SLN administration, the AUC of idarubicin was lower than after duodenal administration of the same formulation. Duodenal administration of IDA-SLN modifies the pharmacokinetics and tissue distribution of idarubicin. The IDA-SLN act as a prolonged release system for the drug.     

羟基喜树碱脂肪乳在大鼠体内的药动学及组织分布研究

目的:研究羟基喜树碱(HCPT)脂肪乳在大鼠体内的药动学及组织分布。方法:采用高效液相色谱法测定静脉注射HCPT脂肪乳后大鼠血浆及组织中HCPT浓度,计算药动学参数并分析药物在组织中的分布情况,并与静脉注射HCPT溶液比较。结果:HCPT脂肪乳和溶液在大鼠体内药动学过程呈二室吸收模型,t1/2α分别为(0.081±0.011)h、(0.517±0.721)h,t1/2β分别为(0.778±0.107)h、(0.3890±0.053)h,AUC(0～4h)分别为(1.619±0.223)μg·h·mL-1、(2.031±0.280)μg·h·mL-1,Cl(S)分别为(114.3±15.7)mL·h-1、(100.3±13.8)mL·h-1;与溶液比较,静脉注射HCPT脂肪乳后HCPT在肝、肺、脾、脑中的浓度更高。结论:与HCPT溶液剂型比较,脂肪乳剂型更能提高药物对肝、肺、脾、脑的趋向性。     

Physiologically based pharmacokinetic model for cefazolin in rabbits and its preliminary extrapolation to man

In the present study, the physiologically based pharmacokinetic model, which succeeded previously in predicting the pharmacokinetics of beta-lactam antibiotics in rats [A. Tsuji, T. Yoshikawa, K. Nishide, H. Minami, M. Kimura, E. Nakashima, T. Terasaki, E. Miyamoto, C.H. Nightingale, and T. Yamana: Physiologically based pharmacokinetic model for beta-lactam antibiotics. I: tissue distribution and elimination in rats. J. Pharm. Sci. 72, 1239-1252 (1983)], was applied to cefazolin pharmacokinetics in rabbits and man. After iv bolus dosing in normal rabbits, the time courses of cefazolin concentration in plasma and various tissues (lung, heart, muscle, skin, bone, gut, liver, and kidney) were found to be very similar to those in rats. The values of physiological parameters (tissue plasma flows, tissue volumes, tissue/plasma albumin ratio) and biochemical parameters determined in this study (for nonlinear plasma protein binding, intrinsic renal clearance of active secretion and reabsorption) were incorporated into mass balance equations derived from the model. There was reasonable agreement between the model predictions and the observed data for cefazolin and inulin in rabbits. The model was also successful in the prediction of cefazolin disposition in rabbits with renal failure. Using available information reported for cefazolin in man, a preliminary extrapolation from the present model was attempted, and the overall predicted results after iv administration of 1 g cefazolin in man were compared with the serum and bone tissue data. The length of the effective antibacterial period for the drug is also discussed in terms of its predicted concentration unbound with proteins in various tissue interstitial fluids in man.