卡巴拉汀脂质体的制备及其大鼠鼻腔给药的药代动力学

制备卡巴拉汀脂质体,研究其在大鼠鼻腔给药的药代动力学。采用硫酸铵梯度法制备包载卡巴拉汀的脂质体,考察粒径、zeta电位和包封率,测定脂质体在磷酸盐缓冲液中的释放;大鼠鼻腔给予卡巴拉汀脂质体,以安替比林为内标,采用高效液相色谱-串联质谱法(HPLC/MS)测定血浆中卡巴拉汀的浓度,运用DAS 2.0软件拟合药代动力学参数。经筛选制备的脂质体包封率为(33.41±6.58)%,平均粒径在154～236 nm,zeta电位(-10.47±2.41)mV。脂质体的体外释放符合一级动力学方程。大鼠鼻腔给药后,Cmax,Tmax和AUC0-∞分别为(1.50±0.15)mg.L-1,15 min和(89.06±8.30)mg.L-1.min。卡巴拉汀制备成脂质体经大鼠鼻腔给药后,吸收迅速,血药浓度可以达到一定水平。     

天麻苷元大鼠鼻腔和静脉注射给药的脑药动学研究

目的:研究比较天麻苷元在大鼠鼻腔给药和静注给药后的血和脑脊液药动学。方法:天麻苷元静注给药剂量为50或10 mg.kg-1,鼻腔给药剂量为10 mg.kg-1。采用高效液相法测定血和脑脊液中天麻苷元的浓度,以DAS 2.0药动学软件计算非房室模型参数。结果:给药后天麻苷元能迅速进入脑脊液中,AUCCSF高于AUCplasma,鼻腔给药的AUCCSF或AUCplasma与静注给药的相比无显著性差异。结论:鼻腔给药后天麻苷元能迅速完整地进入体循环中,鼻腔给药可替代静注给药,未观察到鼻-脑途径的直接传递。     

三七总皂苷鼻腔给药的药代动力学与药效学

目的研究三七总皂苷鼻腔用粉雾剂以混悬液形式给药后在大鼠体内的药代动力学过程及对心脑血管疾病的保护作用。方法HPLC测定三七总皂苷混悬液大鼠鼻腔给药后血样中人参皂苷Rg1的浓度，考察药物在体内的动力学过程，并计算其绝对生物利用度；结扎SD大鼠的左冠状动脉建立急性缺血性心肌梗死模型，夹闭沙鼠的双侧颈总动脉建立脑缺血再灌注模型，考察三七总皂苷混悬液对心脑血管疾病的保护作用。结果三七总皂苷混悬液鼻腔给药后，Rg1在大鼠体内的过程符合二室模型，其绝对生物利用度为103.56％；对大鼠急性缺血性心肌梗死及沙鼠脑缺血再灌注所引起的脑水肿和脑卒中症状均具有明显的缓解作用，且呈剂量依赖性，剂量越高，保护作用越强。结论药代动力学和药效学结果证明，三七总皂苷鼻腔给药制剂具有很好的开发前景。     

阿糖胞苷不同给药途径的药代动力学研究

本文报道25例急性白血病应用HPLC法对Ara-C不同给药途径的药代动力学进行了研究。结果表明:不论何种给药途径Ara-C总体清除率及浓度时间曲线下面积的平均值无差异(P>0.05)。静脉快进推注、肌肉注射及皮下注射给药可使血浆Ara-C浓度达较高水平,但峰值持续时间短、下降快。持续静脉给药,血浆Ara-C维持在30～60ng/ml范围内;持续皮下滴注时维持在30～50ng/ml范围内。髓内用药与静脉用药其药代方式一致。     

肥胖患者体内药代动力学变化及给药方案制定

笔者查找近年国内外相关文献,对肥胖群体体内药物动力学变化进行综述,并对常用药物的给药方案进行评价。结果表明,肥胖患者体内药物分布和代谢均发生改变,从而导致给药剂量的变化,应根据肥胖患者的特点合理应用药物,提高治愈率,减少不良反应的发生,实现个体化给药。     

经皮给药的药代动力学研究进展

经皮给药系统是当今药物传输系统研究的热点。随着该类制剂的广泛应用，其药代动力学的研究也日益深入，取得了一定的进展。本文对经皮给药药代动力学的机制、数据处理模型及其方法学等方面进行了比较详细的介绍。     

组合给药在药代动力学高通量筛选中的应用

组合给药，即同时给动物服用多种药物，可以实现体内高通量筛选，这种方法目前应用不是很广泛，因此有较大的研究空间。该法的实施依赖于现代分析技术的高灵敏度和高选择性，尤其是HPLC／MS／MS联用技术的使用。本文将对组合给药法的实验设计、分析技术及应用状况作一综述。     

冰片对大鼠经鼻腔给药灯盏花素体内药动学的影响

目的:探索冰片对大鼠经鼻腔给药灯盏花素体内药代动力学的影响。方法:采用同位素标记法125I检测实验大鼠经过尾静脉注射、单纯鼻腔给药和鼻腔给药联合冰片三种途径摄入0.4mg/kg灯盏花素以后的药代动力学,测定1、5、10、30、60、90、120、150、180、210、270min的血浆中灯盏乙素的浓度,绘制药时曲线并比较三种途径的药代动力学参数。结果:经鼻腔给药联合冰片组大鼠的tmax为22min短于单纯鼻腔给药组的tmax30min,差异有统计学意义(t=5.73,P=0.025);经鼻腔联合冰片组和单纯鼻腔给药组的Cmax分别为0.55、0.52μg/mL,绝对生物利用度分别为53.21%和53.71%,差异没有统计学意义。结论:冰片可以在一定程度上影响大鼠经鼻腔灯盏花素给药,使其血浆灯盏乙素浓度的达峰时间缩短,但是对灯盏乙素的绝对生物利用度没有明显影响,可以为灯盏花素新制剂的研究提供新方向。     

Pharmacokinetics and brain uptake of diazepam after intravenous and intranasal administration in rats and rabbits

The purpose of this study was to investigate the plasma pharmacokinetics and brain uptake of a lipophilic benzodiazepine anticonvulsant, diazepam in New Zealand white rabbits and Sprague-Dawley rats to evaluate the possible absorption pathways after intravenous and intranasal administration. The intranasal formulation was prepared by dissolving DZ and 1% sodium glycocholate into microemulsion system composed of 15% ethyl laurate, 25% Labrasol, 37.5% Transcutol P, 12.5% ethanol, and 10% water. Diazepam was administered intravenously (1 mg/kg) or intranasally (2 mg/kg) to rats and rabbits. Drug concentrations in the plasma and six different regions of the brain tissues, i.e., olfactory bulb, olfactory tract, anterior, middle, and posterior segments of cerebrum and cerebellum were analyzed by LC/MS method after solid phase extraction. After i.n. administration, DZ was rapidly absorbed into the systemic circulation, and readily and homogeneously distributed into the different regions of brain tissues with a t(max) of 5 and 10 min in rats and rabbits, respectively. The bioavailability of DZ in rat plasma (68.4%) and brain (67.7%) were 32-47% higher than those observed in rabbit plasma (51.6%) and brain (45.9%). The AUC(brain)/AUC(plasma) ratios in rabbits after i.n. administration (3.77+/-0.17) were slightly lower than from i.v. administration (4.23+/-0.08). However, in rats the AUC(brain)/AUC(plasma) ratios after i.v. (3.03+/-0.07) and i.n. (3.00+/-0.32) administration were nearly identical. The plasma pharmacokinetic and distribution studies in the two animal models clearly showed that lipophilic DZ molecules reached the brain predominantly from the blood by crossing the blood-brain barrier after i.n. administration with no significant direct nose-to-brain transport via olfactory epithelium.     

Pharmacokinetics of verproside after intravenous and oral administration in rats

Verproside, a catalpol derivative iridoid glucoside isolated from Pseudolysimachion longifolium, is a candidate for anti-asthmatic drug. The dose-dependency of the pharmacokinetics of verproside was evaluated in rats after intravenous and oral administration. After intravenous administration of verproside (2, 5 and 10 mg/kg doses), the systemic clearance (Cl) was significantly reduced and AUC was significantly increased at 10 mg/kg dose compared to 2 and 5 mg/kg doses. The volume of distribution at steady state (V _ss) remained unchanged as the dose was increased. The extent of urinary excretion was low for both intravenous (3.3–6.2%) and oral (0.01–0.04%) doses. Isovanilloylcatalpol was identified as a metabolite after intravenous administration of verproside and showed the significant decreases in AUC and C _max at 10 mg/kg verproside dose. The reduced systemic clearance of verproside at high doses appears to be due to the saturable metabolism. Upon oral administration of verproside (20, 50 and 100 mg/kg doses), C _max was nonlinearly increased. The extent of verproside recovered from the gastrointestinal tract at 24 h after oral administration was 0.01–0.72% for all three doses studied. The absolute oral bioavailability (F) was 0.3 and 0.5% for 50 and 100 mg/kg doses, respectively. Low F appears to be due to first-pass metabolism.     

Pharmacokinetics of methylprednisolone after intravenous and intramuscular administration in rats

Methylprednisolone (MPL) pharmacokinetics was examined in adrenalectomized (ADX) and normal rats to assess the feasibility of intramuscular (i.m.) dosing for use in pharmacodynamic studies. Several study phases were pursued. Parallel group studies were performed in normal and ADX rats given 50 mg/kg MPL (i.v. or i.m.) and blood samples were collected up to 6 h. Data from studies where normal rats were dosed with 50 mg/kg MPL i.m. and killed over either 6 or 96 h were combined to determine muscle site and plasma MPL concentrations. Lastly, ADX rats were dosed with 50 mg/kg MPL i.m. and killed over 18 h to assess hepatic tyrosine aminotransferase (TAT) dynamics. MPL exhibited bi-exponential kinetics after i.v. dosing with a terminal slope of 2.1 h(-1). The i.m. drug was absorbed slowly with two first-order absorption rate constants, 1.26 and 0.219 h(-1) indicating flip-flop kinetics with overall 50% bioavailability. The kinetics of MPL at the injection site exhibited slow, dual absorption rates. Although i.m. MPL showed lower bioavailability compared with other corticosteroids in rats, TAT dynamics revealed similar i.m. and i.v. response profiles. The more convenient intramuscular dosing can replace the i.v. route without causing marked differences in pharmacodynamics.     

Pharmacokinetics of dihydroergosine in rats after intravenous and oral administration

Wistar rats received an intravenous dose of 20 micrograms/kg and an oral does of 40 micrograms/kg 3H-Dihydroergosine. Concentrations of radioactivity were measured in plasma, bile, urine, and faeces, and pharmacokinetical parameters of an open two compartment model were calculated. After intravenous injection and oral administration 3H-Dihydroergosine is rapidly lost from the central compartment with distribution rate constants alpha = 0.889 h-1 and beta = 0.722 h-1, respectively. Biological half life in the elimination phase after both application is nearly the same t 1/2 = 13.6 h. The volume of central compartment is Vc = 3.075 l/kg and the volume of distribution Vd beta = 30.75 l/kg. The fraction of 3H-Dihydroergosine absorbed after oral administration, calculated from areas under the curves upon oral and intravenous administration, is 31%. The percentage of 3H-radioactivity eliminated with bile was 98.3% of the dose within 72 hours after intravenous and 29.3% after oral administration. The main portion of the administered 3H-radioactivity was recovered in faeces -66.1% after intravenous and 81.3% after oral administration, while only 17.4% and 4.9% of the administered dose was eliminated in the urine within 120 hours, respectively.     

Pharmacokinetics of baicalin-phospholipid complex in rat plasma and brain tissues after intranasal and intravenous administration

The aim of this study is to determine whether baicalin can be transferred along the olfactory pathway to the brain after nasal administration of baicalin phospholipid (BP) complex to rats, thereby circumventing the blood brain barrier. The concentration of baicalin in plasma and different brain tissues (olfactory bulb, cerebral cortex, striatum and cerebellum) were measured by high-performance liquid chromatography (HPLC). The ratios of the area under the concentration-time curve (AUC) values of intranasal to intravenous administrations were 54.21%, 240.59%, 374.71%, and 114.54% in plasma, cerebral cortex, striatum, and cerebellum, respectively. In the olfactory bulb, the AUC values of intranasal to intravenous administrations were 3355.4 +/- 378.8 microg/g-min versus 0 microg/g x min following intravenous administration. The ratios of AUC values of intranasal to intravenous administrations were72.75 %, 240.59 %, 374.71%, 114.54% in plasma, cortex, striatum, cerebellum respetively. The proportion of baicalin in the brain tissues from the olfactory transfer was also calculated, and the result shows that, following intranasal administration, approximately 52.36%-100% baicalin content at 8 h was transported to the brain via the olfactory pathway. In conclusion, the BP complex is transferred into the olfactory bulb via the olfactory pathway in rats, and the BP complex intranasal delivery is a promising approach to protect against cerebral ischemic injury.     

Pharmacokinetics of glycyrrhizin after intravenous administration to rats.

A simple high-performance liquid chromatographic method was developed to study the pharmacokinetics of glycyrrhizin in the rat after bolus intravenous administration at a dose of 20, 50, or 100 mg/kg. The decline in the concentration of glycyrrhizin in plasma was generally biexponential at each dose, but the terminal disposition became much slower as the dose was increased. A greater-than-proportional increase in the glycyrrhizin concentration in plasma was observed with an increase in the dose, a result suggesting a dose-dependent glycyrrhizin disposition. The disposition of drug in plasma at each dose fitted well to a two-compartment pharmacokinetic model. The apparent total body clearance decreased significantly with increases in the dose. On the other hand, the apparent distribution volume after intravenous administration was unaffected by the dose. The results indicate that the pharmacokinetics of glycyrrhizin is nonlinear.     

Pharmacokinetics of fentanyl in male and female rats after intravenous administration

The sex difference of fentanyl (CAS 990-73-8) pharmacokinetics was investigated after intravenous administration to male and female rats at a dose of 0.03 mg/kg. The plasma concentrations of fentanyl disappeared mono-phasically in both male and female rats. Plasma concentrations and pharmacokinetic parameters were not significantly different in male and female rats, but plasma concentrations of fentanyl in female rats were lower than those in male rats until 1 h after administration. The distribution volume in female rats was 1.34 times larger than that in male rats. In a previous study, the C(max) and AUC(0-infinity) values in female rats were significantly lower than those in male rats after subcutaneous administration of fentanyl. Since no sex difference in the pharmacokinetic parameters of fentanyl were observed after intravenous administration in the present study, the sex difference of the pharmacokinetics of fentanyl after subcutaneous administration may be explained by delayed distribution from the dosing site to the systemic circulation in female rats relative to male rats, which may be attributable to a higher content of subcutaneous fat in female rats.     

Pharmacokinetics of imipramine after single and multiple intravenous administration in rats

Plasma and brain levels of imipramine (IMI) and desmethylimipramine (DMI) in rats after single and multiple iv administration were estimated. IMI accumulated only in plasma, while DMI accumulated in plasma and brain of rats. The brain level of IMI and DMI was higher than plasma level. After multiple administration plasma DMI concentration was significantly greater than IMI concentration. It seems that IMI was obtained steady-state plasma concentration already at fifth day of multiple administration. High dose of IMI (10 mg/kg) caused that the relationship between steady-state concentration and dose of IMI cannot be expressed as a linear function.