重组人肿瘤坏死因子-α衍生物在小鼠体内的药代动力学和组织分布

采用放射性测量法检测了小鼠血浆和组织中人肿瘤坏死因子-α衍生物(rhTNF-B)的浓度.以Iodogen法制备125I-rhTNF-B,将其静注小鼠后呈二房室模型处置特征,分布半衰期平均为2.81±0.62 min,消除半衰期平均为25.3±5.0 min,中央室分布容积为17.8±2.3 ml.静注后125I-rhTNF-B可很快向机体的各组织分布,大多数组织在3 min即达到较高浓度,其中以肝脏浓度最高,肺,肾,心,胃,脾,小肠,皮肤等组织也有较高的浓度;而肌注125I-rhTNF-B后大多数组织在给药60 min后达高峰.各组织脏器的 4 h放射性累积量在iv组依次为肝＞肾＞肺＞小肠＞胃＞脾＞心＞皮肤＞肌肉＞脑,在im组依次为:肾＞胃＞肝＞肺＞皮肤＞小肠＞心＞脾＞肌肉＞脑.     

落新妇苷固体分散体在大鼠体内的药动学研究

目的 研究大鼠口服落新妇苷固体分散体后的药物动力学参数。方法 采用HPLC法测定大鼠口服落新妇苷固体分散体后血浆中的落新妇苷血药浓度。用kinetica软件计算动力学参数。结果 落新妇苷在大鼠体内的药物动力学过程符合二室模型。AUC0-480min为1.98±0.60 mmol?min?L-1。结论 将落新妇苷制成固体分散体可以显著提高其生物利用度。     

射干提取物在大鼠体内分布研究

目的研究射干提取物在大鼠体内的组织分布特征。方法射干提取物给大鼠灌药后,以鸢尾黄素为研究指标,采用高效液相色谱法测定其在大鼠心、肝、脾、肺、肾中的含量。结果鸢尾黄素在大鼠体内各部分的分布顺序为：肝〉肾〉肺〉心〉脾。结论射干提取物中鸢尾黄素在大鼠体内分布广泛,在肝肾肺组织中药物浓度较高,并且在肺组织中达到平衡后能较长时间保持药物浓度,与射干药材归肺经相符合,提示鸢尾黄素可能是射干用于治疗上呼吸道作用的药效物质之一。     

注射用纳米羟喜树碱与注射用羟喜树碱在小鼠体内的组织分布比较

目的:观察注射用纳米羟喜树碱(HCPT纳 米针剂)静脉推注后小鼠体内组织分布情况,并与 注射用羟喜树碱(HCPT针剂)比较组织分布特征。 方法:BALB/c小鼠分别给予HCPT纳米针剂或 HCPT针剂,10mg·kg-1尾静脉推注给药。给药后 15min,1和2h,采用HPLC方法检测小鼠各组织和 血浆中羟喜树碱的含量,并对不同剂型和不同取样 时间进行比较。结果:(1)HCPT纳米针剂在肝组 织中浓度最高,分布顺序:肝>肾>脾>肠>胃> 肺>心。(2)HCPT纳米针剂在肝、肾、脾、肺、胃的 药物浓度均显著高于HCPT针剂(P<0.05),肝组 织药物浓度最高,是HCPT针剂组的37.66倍 (15min)。(3)HCPT纳米针剂给药后在肝组织保 留时间长,而HCPT针剂组给药后没有显著蓄积的 靶组织。结论:HCPT纳米针剂与HCPT针剂相比, 能够更多地进入组织器官并具有明显的肝组织靶向 性,在肝组织中可较长时间保持较高药物浓度。     

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。     

落新妇苷对心脏移植排斥反应中活化T细胞p38丝裂原激活蛋白激酶信号传导通路的影响

目的：用小鼠心脏移植急性排斥反应体外模型，探讨落新妇苷对心脏移植排斥反应中活化T细胞p3S丝裂原激活蛋白激酶（p38MAPK）信号传导通路的影响。方法：分离BALB／C小鼠心肌细胞（2×10^5个·mL^-1）和C57BL／6小鼠的睥细胞（1×10“个·mL^-1），前者做刺激细胞，后者做反应细胞，进行混合细胞培养，建立小鼠心脏移植急性排斥反应体外模型。实验分3组：对照组，心肌细胞与脾细胞混合培养；落新妇苷组，在对照组基础上加入落新妇苷（15mg·L^-1）；落新妇苷加p38MAPK抑制剂组，在对照组基础上加入落新妇苷（15mg·L^-1）和p38MAPK抑制剂SB203580（5μmol·L^-1）。TUNEL法检测T淋巴细胞凋亡情况。RT-PCR和Western blot法检测T细胞p38MAPK表达情况。结果：落新妇苷组T细胞凋亡指数和p38MAPK表达均明显高于对照组（P＜0．01）。落新妇苷加p38MAPK抑制剂组T细胞凋亡指数和p38MAPK表达均明显低于落新妇苷组（P＜0．01），而与对照组相比差异无显著性（P＞0．05）。结论：落新妇苷诱导心脏移植排斥反应中活化T细胞凋亡与其激活p38MAPK信号传导通路有关。     

喜树碱前体的药物动力学研究

用沉淀荧光法研究了喜树碱前体（A-CPT）在小鼠体内的药物动力学。结果表明，A-CPT在小鼠体内的血药浓度经过过程符合三隔室开放模型，其α、β及γ相的半衰期分别为1.8，64.5及852min;Vc及Vd分别为4.63±10^-3及0.741;C1及AUC分别为6.07×10^-4l/min及2082ug.min/ml;MRT为999min，组织分布研究表明，静脉注射给药后24h内的组织浓度时间曲线下面积按照肠（含内容物），骨（含髓），肾，脑，肝（含胆），胃（含内容物）肺，脾，血及心的顺序依次递减，除胃、肠的组织浓度时间曲线有浓度峰以外，其它组织的浓度时间曲线呈单调下降的趋势。     

α-与β-甘草酸在小鼠体内分布的研究

目的 :探讨甘草酸 (glycyrrhizicacid ,GL)的两个差向异构体α GL和 β GL在小鼠体内的分布及其特征。方法 :运用HPLC UV法检测小鼠单次ivα GL或 β GL5 3mg·kg-1后 5、15、30、6 0和 180min时体内各组织脏器中的药物含量 ,比较、评价两者的分布差异及特征。结果 :α GL和 β GLiv后分布迅速 ,除血外 ,肝中含量最高 ,肺、肾、脂肪、心、卵巢、肠、脾、睾丸、肌肉中药物含量依次减小 ,脑中最低 ;肠肝循环的第二峰现象出现在 30min时 ;α GLiv后早期肝含量显著高于 β GL ,血及其余组织脏器药物含量明显低于 β GL或与其相近 ;随时间的延长药物含量迅速降低的同时肠浓度渐高 ,至 180min时α GL各组织脏器 (除肠外 )药物浓度接近或低于检测限 ,β GL则仍维持较高浓度 ,是峰值的 30 %～ 70 %。结论 :小鼠ivα GL后在体内呈肝分布特异性 ,转化成GA的速率高于 β GL ,无组织蓄积 ;而 β GL在体内分布广泛 ,代谢较慢 ,有蓄积的可能     

首乌苷制剂中二苯乙烯苷含量测定及其在小鼠体内组织分布研究

目的建立首乌苷制剂中二苯乙烯苷（TSG）含量测定方法;观察其在小鼠体内的组织分布。方法采用反相高效液相色谱法,色谱柱：Agilent XDB C18（150 mm×4.6 mm,5μm）,流动相：乙腈-水（20∶80）;检测波长：320 nm。取小鼠,灌胃给予首乌苷样品溶液60 min后放血处死,取心、肝、脾、肺、肾、脑、睾丸,制备组织匀浆,甲醇除蛋白,测定各脏器中TSG的含量。结果 TSG在0.053～0.489μg内线性关系良好（r=0.9993）,低、中、高浓度的回收率分别为（101.6±1.3）%,（100.9±2.3）%,（100.8±2.4）%。TSG在肝组织中分布最多,其次为肺、肾、心等。结论 TSG含量测定方法简便可靠、重复性好,可用于首乌苷制剂的质量控制。TSG在小鼠多个脏器中均有分布,以肝脏中分布最多,可通过血脑屏障。     

反义核酸药物KS0604在小鼠的组织分布

目的:研究小鼠静脉注射30 mg.kg-1 KS0604后血浆和组织中原形药物浓度-时间变化。方法:建立组织消化结合基于离子交换和反相分配原理的两步固相萃取法,并采用非胶筛分毛细管电泳技术分析小鼠血浆和组织中的KS0604。结果:小鼠血浆和组织中KS0604在标准曲线范围内呈良好的线性关系。小鼠给药后各组织中以全长序列即药物原形为主,给药后4 h内,血浆中的浓度逐渐下降,2 h和4 h仅个别个体可测到。各组织中肾浓度一直最高,在给药后2 h达峰;肝、肺、心、骨骼肌和脂肪中,均在给药后1 h达到最高,4 h内变化不大。而脾在给药后仅个别个体可测到,脑和胰组织中的浓度均低于定量下限。结论:非胶筛分毛细管电泳方法能满足反义核酸药物KS0604小鼠组织分布实验的要求。小鼠给药后各组织中以全长序列即药物原形为主,给药后4 h内,AUC0～t从大到小依次为肾、肝、肺、心、骨骼肌、脂肪和血浆。     

Population pharmacokinetics–pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex

Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5–15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustments. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure mean was implemented as an asymptotic exponential function of time leading to a new steady-state seizure mean. The everolimus effect was implemented as an inhibitory E_max function of C_min on the seizure mean, where E_max exhibited an asymptotic exponential increase over time to a higher steady-state value. Increasing age was found to decrease the baseline seizure mean and to prolong the half-life of the increase in E_max. The dependence of seizure frequencies on C_min was explored by simulation. The responder rate increased with increasing C_min. As C_min decreased below 5 ng/mL, variability in response became larger and responder rates decreased more rapidly. The results supported the recommended target concentration range for everolimus of 5–15 ng/mL to ensure treatment efficacy.     

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Objectives

To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC).

Methods

Open-label, randomized, two-period, active-controlled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson’s disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included C_min, C_max, C_max???C_min, AUC, t_1/2, and t_max.

Results

In healthy volunteers and PD patients, mean trough levels (C_min), C_max, and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to C_min, C_max, and AUC, differences between the treatments in variability of levodopa concentrations (C_max???C_min) were less consistent.

Conclusions

The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson’s disease using similar dosing regimens.     

桔梗总皂苷对左氧氟沙星在小鼠体内的药动学及组织分布的影响

目的 采用高效液相色谱（HPLC）法测定小鼠血浆及组织中左氧氟沙星含量,研究桔梗总皂苷对其药动学规律及组织分布的影响。方法 180只昆明小鼠随机分为两组,组Ⅰ为单独ig左氧氟沙星78 mg/kg,组Ⅱ为同时ig桔梗总皂苷65 mg/kg与左氧氟沙星78 mg/kg,采用HPLC法测定给药5、15、30、45 min及1、1.5、2、4、8 h后的血浆及肝、肺、肾组织样品中的左氧氟沙星浓度。结果 血浆中内源性物质对待测物无干扰;血浆及各组织在检测浓度范围内呈良好线性关系（r²>0.999）;方法日内和日间精密度、稳定性及提取回收率均符合生物样品检测标准;组ⅠAUC_0-t为（143.593±16.56）,组ⅡAUC_0-t为（120.339±15.542）,与组Ⅰ比较,组Ⅱ的AUC明显减小,T_1/2Z显著缩短,T_max明显延长,CLz/F显著增加,C_max及Vz/F无显著性差异;肝、肺、肾组织中左氧氟沙星浓度均迅速提高并快速消除,肺组织中消除速度最快,肺中AUC减少最为明显。结论 合用时,桔梗总皂苷使左氧氟沙星在小鼠体内消除速率明显加快,肺组织中尤为明显,故左氧氟沙星在联合含有桔梗成分的中药治疗肺部疾病时,建议分开服用。     

田口设计筛选硝苯地平喷雾干燥分散体的处方研究

目的 考察喷液处方对硝苯地平喷雾干燥分散体（spray dried dispersion,SDD）的表征和非漏槽条件下溶出度的影响。方法 采用minitab DOE（design of experiment）中的田口设计（Taguchi design）方法,以120 min以内的溶出度曲线下面积（AUC0~120 min）及120 min时的溶出浓度和最大浓度的比值（C₁₂₀/C_max）为评价指标,考察载体材料的种类和用量及喷雾溶液的固含量对硝苯地平SDD的药物存在状态和体外溶出度的影响。结果 硝苯地平与聚合物的比例对固体分散体中药物的存在状态和体外溶出度均有显著影响,固含量对结果影响较小。以共聚维酮为载体材料时,可以获得比醋酸羟丙甲基纤维素琥珀酸酯（HPMCAS）更高的最大溶出浓度（C_max）,但是HPMCAS的抑制药物重结晶的效果明显优于共聚维酮,其中药物-HPMCAS LG 1∶4时可以获得最大的C_max和AUC_{0~120 min}。结论 硝苯地平与HPMCAS LG按照1∶4的比例配成固含量10%的溶液进行喷雾干燥,可以制得溶出度显著改善的SDD。     

Influence of the rate of intravenous administration of eliprodil (SL 82.0715), a new anti-ischaemic agent,on its distribution in rat plasma and tissues

This investigation studied the possible effect of different iv administration rates (bolus and infusions) of eliprodil, a new anti-ischemic agent, on the drug distribution in various body compartments. Following bolus administration of a 15-mg kg⁻¹ dose, plasma concentrations were best fitted by a 3-compartment open model of t_1/2α=14 sec, t_1/2β=4 min, and t_1/3γ=1.8 hr. Plasma and heart C_max values were lowered by decreasing the infusion rate (the 15-mg dose was administered in 15 or 60 min) whereas brain C_max values were not modified. In contrast, AUC values did not depend upon the rate of infusion. The present findings may have important implications in relating tissue concentrations with the desired therapeutic effect as well as with the side effects of the drug at its sites of action within brain and heart. The use of a simplified model built with plasma and tissue kinetic parameters following bolus injection allows one to predict the amount of drug present in the organs according to the mode of administration, but not the evolution of tissue to plasma ratio during the infusions.     

Time-dependent variation in the biodistribution of C₆₀ in rats determined by liquid chromatography-tandem mass spectrometry

We examined the biodistribution of C₆₀ in rats after tail vein administration using LC-MS/MS. C₆₀ was detected in various tissues, such as brain, kidneys, liver, lungs, and spleen of rats. On the other hand, no C₆₀ was found in blood. The highest C₆₀ concentration was observed in the lungs, followed by spleen, liver, kidneys, and brain. These results suggested that C₆₀ injected in the tail vein could be filtered by lung capillary vessels and accumulate in the lungs prior to being distributed to other tissues. Moreover, C₆₀ not being detected in the blood indicates that clearance of C₆₀ from the blood by filtration might effectively occur in the lungs. The time-dependent variation in the biodistribution of C₆₀ was evaluated. A time-dependent decrease in C₆₀ concentrations was observed in all tissues, except spleen. Moreover, a decreasing trend of C₆₀ levels differed among tissues, which could be due to differences in accumulation. These results suggest that unmodified C₆₀ and/or C₆₀ metabolites by metabolic enzymes could be excreted into feces and/or urine. In further studies, the metabolic and excretion pathways of C₆₀ should be evaluated to understand the toxicokinetics of C₆₀.     

Why Rate of Absorption Inferences in Single Dose Bioequivalence Studies are Often Inappropriate

Purpose. Peak drug concentration (C_max) measures the extremity of drug exposure and is a secondary indicator of the extent of absorption after area under the concentration time curve (AUC). C_max serves as the indicator of absorption rate in bioequivalence (BE) studies in the US (1). The use of C_max, not the time to Cmax(Tmax), as the metric to assess absorption rate causes erratic inferences in BE studies, and incorrect conclusions for some. We can improve BE efficiency (i.e., get the answer right the first time), by properly analyzing the time to C_max(T_max) instead of C_max. Methods. We have previously redirected attention to T_max as the unconfounded absorption rate variable, instead of Cmax, and have called for equally spaced sampling times during the suspected absorption phase to improve the performance of the rate metric (2). Equal spacing converts T_max easily into a count variable and we illustrated an appropriate statistical analysis for counts. This paper provides some measurement theory concepts to help judge which is the more appropriate analysis, and also provides parametric confidence limits for T_max treatment differences. Three separate BE studies are then analyzed by both methods. Results. By focusing on the differences in conclusions, or inferences, this paper identifies three major issues with the current FDA "recommended analysis of BE studies. First, C_max, a continuous variable peak-height or extent measure has usurped T_max's function and performs erratically as a substitute measure for the rate of absorption. Second, T_max, should be analyzed as a discrete attribute, not as a continuous variable. Third, since several extent measures (AUC, C_max), not one, are actually being analyzed, an adjustment for multiple testing is mandatory if we are to maintain the size of the test at the desired level (13), and not inadvertently use a narrower bioequivalence window than is intended. These actions all can have serious unintended consequences on inferences, including making inappropriate ones.     

Risk factors associated with high linezolid trough plasma concentrations

Aim: The major concern of linezolid is the adverse events. High linezolid trough serum concentration (C_min) has been associated with toxicity. The aim of this study was to analyze factors associated with high C_min.

Methods: Main clinical characteristics of 104 patients treated with 600 mg/12 hours of linezolid were retrospectively reviewed. Samples were obtained just before the next dose after at least three doses and within the first 8 days of treatment. High C_min was considered when it was >8 mg/L. Univariate and multivariate analysis were performed.

Results: 34.6% patients had a C_min >8 mg/L, and they were older and had more frequently an estimated glomerular filtration by MDRD <40 mL/min. There were more patients co-treated with rifampin in the group with low C_min. The only factor independently associated with C_min >8 was the renal function. Patients with an eGF < 40 mL/min had significantly higher C_min than those with eGF > 80 mL/min (OR: 4.273) and there was a trend towards a high C_min in patients with eGF between 40-80 mL/min (OR: 2.109).

Conclusions: High C_min were frequent, especially in patients with MDRD <40 mL/min. Therapeutic drug monitoring could be useful to avoid toxicity in patients with renal dysfunction.     

重症患者替加环素血药浓度的监测与PK/PD达标率的研究

目的对使用替加环素治疗的重症患者血药浓度进行监测,计算其PK/PD达标率,为临床更加合理地使用替加环素提供参考。方法采用回顾性分析方法,将纳入的45例重症患者分为高、低剂量组,收集第7次给药后的谷浓度、中浓度及峰浓度(Cmin、C1/2t、Cmax),计算2组AUC0-24、AUIC值及不同感染部位PK/PD达标率,观察2组不良反应情况。结果高剂量组的Cmin、C1/2t、Cmax、AUC0-24及PK/PD总达标率均显著高于低剂量组(P<0.05)。高剂量组在肺部、腹腔、皮肤及软组织感染的达标率均高于低剂量组,其中2组在肺部感染的达标率具有显著性差异(P<0.05)。2组随着病原菌最低抑菌浓度(minimum inhibitory concentration,MIC)的增高,PK/PD达标率显著下降。45例患者中发生不良反应共7例,2组不良反应的发生率无显著性差异。结论替加环素对重症患者安全性较好,对于重症患者肺部感染和皮肤及软组织感染,特别是具有高MIC的病原菌感染,可适当地提高替加环素的剂量。     

PHARMACOKINETICS AND FOOD INTERACTION OF MK-462 IN HEALTHY MALES

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5–90 μg kg⁻¹of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 μg kg⁻¹ are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 μg kg⁻¹. The values of the plasma clearance (CL), steady-state volume of distribution (V_ss), plasma terminal half-life (t_½), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min⁻¹, 140 L, 1·8 h, and 1·7 h, respectively, and remained essentially constant over the dosage range of 10–60 μg kg⁻¹ of IV MK-462. However, as the dose increased from 60 to 90 μg kg⁻¹, the mean value of the apparent CL decreased from 1376 to 807 mL min⁻¹. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the V_ss value of MK-462 remained essentially constant over the dosage range of 10–90 μg kg⁻¹ of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CL_d=2028 mL min⁻¹, and mean transit time in the peripheral tissues (MTT_T )=0·74 h. The mean values of AUC, C_max, t_max, and apparent t_½ of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng·h mL⁻¹, 77 ng mL⁻¹, 1·6 h, and 1·8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by ≈20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of C_max and apparent t_½ of MK-462.