反相高效液相色谱法对大鼠体内菲达司他的药代分析

建立反相高效液相色谱（RP—HPLC）测定大鼠血浆中菲达司他浓度的方法,在此基础上对菲达司他在大鼠体内的药代动力学进行初步研究。菲达司他的血浆样品利用乙酸乙酯提取法进行处理,色谱检测条件为用安捷伦Zorbax Eclipse XDB C18色谱柱,紫外检测波长200nm,流动相中v（水）：v（甲醇）为72．28,流速1mL／min,柱温30℃。建立的RP—HPLC法线性范围为0．8～400ug／mL（R=0．9997）。提取回收率大于95％,日内、日间精密度相对标准差（RSD）小于2％。本法简便、准确,适用于菲达司他药代动力学的研究;菲达司他在大鼠体内的药代动力学过程二室模型．     

关于举办“全国新药药代动力学学术研讨会”的通知

国家食品药品监督管理局培训中心和中国临床药理学与治疗学杂志社将于 2 0 0 4年 10月 12 - 16日在深圳共同主办“全国新药药代动力学学术研讨会”。现将有关事项通知如下 :一、参加人员从事新药研究的科研院所有关人员 ,制药企业新药研发部门有关人员 ,临床药理基地从事Ⅰ期临床试验的研究者、临床药学工作者。二、研讨内容1 新药药物代谢动力学研究背景知识介绍 ;2 药物及其代谢物浓度测定的现代仪器特点及其选择 ;3 新药药代动力学申报资料中的问题 ;4 新药临床药代动力学设计和实施要求 ;5 新药非临床药代动力学设计和实施要求 ;6 …     

评价白蛋白相关药物动物模型的研究进展

许多肽或蛋白质药物治疗的一个主要挑战是血浆半衰期短。通过将该类药物与白蛋白结合获得的药物称为白蛋白相关药物，有效延长血浆半衰期。动物模型作为研究药物药代动力学的重要工具是药物研究中不可或缺的一部分。本综述概括了两大类动物模型：啮齿类(野生型小鼠、大鼠模型，基因修饰小鼠模型)与非啮齿(猴)在白蛋白相关药物药代动力学研究中的应用与发展，为其进一步研究发展提供参考。     

绒盖牛肝菌酸HPLC检测方法的建立及在大鼠体内的药代动力学

为建立绒盖牛肝菌酸血药浓度和各主要组织的HPLC检测方法,考察绒盖牛肝菌酸在大鼠体内的药代动力学和组织分布特点。采用Agilent ZORBAX Eclipse XDB-C18 column色谱柱(4.6 mm×250 mm,0.5μm)分离,以V(甲醇)∶V(水)=75∶25为流动相,流速1.0 m L/min,柱温25℃,检测波长243 nm。研究结果表明大鼠血浆及肝组织中的内源性物质均不干扰样品的测定,线性关系良好,大鼠灌胃绒盖牛肝菌酸符合一室模型,主要药代动力学参数Tmax为(0.76±0.21)h,Cmax为(8.76±0.81)μg/m L,t1/2为(0.18±0.28)h,AUC0-inf为(102.95±0.78)μg/(m L·h),大鼠尾静脉注射绒盖牛肝菌酸符合二室模型,主要药代动力学参数t1/2为(0.33±0.71)h,AUC_(0-inf)为(34.14±2.38)μg/(m L·h)。该方法简单快速,准确可靠,符合生物样品的测定要求,并明确了绒盖牛肝菌酸在大鼠体内的药代动力学和组织分布特征。     

斑节对虾血淋巴中诺氟沙星含量测定及药代动力学

采用Agilent 110 0液相色谱仪测定斑节对虾血淋巴中诺氟沙星含量 ,并初步研究了斑节对虾一次性肌肉注射诺氟沙星的药代动力学 ,斑节对虾血淋巴药 时曲线可以用开放性二室模型来描述。由此推算诺氟沙星的药动学参数 ,分布和消除半衰期分别为 0 .0 6 35和 0 .6 12h ;曲线下面积 (AUC)、总体消除率 (CLs)和表观分布容积 (Vd)分别为 12 .42 5ug·h/mL、80 4.83mL/kg·h和 710 .35mL/kg。     

对德氏乳杆菌DM8909菌株的临床药代动力学研究

本文对大连医科大学微生态学研究所研制的阴道乳杆菌活菌制剂进行药代动力学研究 ,目的是为了探讨德氏乳杆菌活菌阴道制剂在正常志愿者阴道中的变化情况 ,确定临床观察的给药剂量、间隔时间和给药方法。现将有关试验情况报告如下 :1　材料与方法1 .1　药代动力学试验研究对象　为 1 0名志愿者进行阴道乳杆菌活菌动态研究。1 .2　药品来源　定菌生 DM890 9由大连医科大学科达药业有限公司提供 ,批号 961 0 2 0。1 .3　试验设计　分 3个剂量组 ,单次阴道给药 ,低剂量组 ( 0 .2 5× 1 0 6CFU/粒 )、中剂量组 ( 0 .2 5×1 0 7CFU/粒 ) ;高剂…     

停用TTS后的贮库模型及计算机模拟

本文建立了停用TTS后的角质层药物贮库模型,並籍此模型的解解析设计计算机程序,对形成角质层药物贮库的TTS的体内药物动力学过程进行摸拟,证实了停用TTS后,中心室药量水平先下降,然后上升形成第二峰,而且第二峰药量水平接近拟稳态药量水平。因此,从理论上解释了形成角质层药物贮库的TTS在停用以后,仍能发挥一段时间的治疗作用的临床观察。此外,还分析了这类药物的临床给药方案。     

基于遗传算法的谷氨酸发酵动力学参数估计

把遗传算法应用于求解谷氨酸分批发酵动力学模型参数,取交叉概率Pc=0．8、变异概率Pm=0．06、初始种群为20、遗传世代数为200代,能进一步提高谷氨酸分批发酵过程状态变量的计算值与实验值的吻合程度。模拟值与实验值对比显示,该动力学模型能很好地反映谷氨酸分批发酵过程。     

定量检测猕猴血清中重组人源化抗狂犬病毒单克隆抗体间接ELISA法的建立

目的：建立定量检测血清中重组人源化抗狂犬病毒单克隆抗体（HuMabs）NM57的间接ELISA法,为药代动力学研究提供一种简单快速的方法。方法：采用狂犬病毒糖蛋白包被酶标板、HRP标记的IgG-Fc段为标记抗体,建立定量检测HuMabsNM57的间接ELISA法,并对其特异性、灵敏度、精密度及准确度进行检测。结果：间接ELISA法检测HuMabsNM57的灵敏度为5ng／mL,组内及组间精密度分别为2．6％-6．0％、8．5％-11．3％。结论：建立了灵敏度高、特异性强的检测HuMabs NM57的间接ELISA法,精密度及准确度均符合药代动力学要求,可用于猕猴及人血清中HuMabsNM57的检测。     

生物技术药物药代动力学研究的方法学和实验设计

生物技术药物由于自身具有的特点 ,使得其在体内的药代动力学机制比传统药物更为复杂。近年来 ,对于这类药物在体内的代谢机制的研究日趋增加 ,研究方法也日趋成熟。概述了生物技术药物的药代动力学研究方法以及实验设计的特点。     

不同给药途径的治疗性纳米抗体研究进展

骆驼科及鲨鱼科动物血清中天然存在的纳米抗体具有不同于传统单克隆抗体的独特结构和分子量,这为抗体药物开发提供了全新的思路。纳米抗体较小的分子量和优异的稳定性使其在给药方面具有更大的灵活性,可以在一定程度上克服传统单克隆抗体在给药途径方面存在的局限性。同时,较小的分子量使纳米抗体具有双重药代动力学特征,既有优异的组织渗透性,又表现出快速的血液清除。重点介绍纳米抗体的药物代谢动力学特征和进一步改善药代动力学的方法,综述不同给药途径的纳米抗体药物研究进展,对其治疗特定疾病的可行性、安全性以及治疗效果进行分析,以期为纳米抗体药物研发中给药途径的选择提供参考。     

A mechanistic framework for a priori pharmacokinetic predictions of orally inhaled drugs

The fate of orally inhaled drugs is determined by pulmonary pharmacokinetic processes such as particle deposition, pulmonary drug dissolution, and mucociliary clearance. Even though each single process has been systematically investigated, a quantitative understanding on the interaction of processes remains limited and therefore identifying optimal drug and formulation characteristics for orally inhaled drugs is still challenging. To investigate this complex interplay, the pulmonary processes can be integrated into mathematical models. However, existing modeling attempts considerably simplify these processes or are not systematically evaluated against (clinical) data. In this work, we developed a mathematical framework based on physiologically-structured population equations to integrate all relevant pulmonary processes mechanistically. A tailored numerical resolution strategy was chosen and the mechanistic model was evaluated systematically against data from different clinical studies. Without adapting the mechanistic model or estimating kinetic parameters based on individual study data, the developed model was able to predict simultaneously (i) lung retention profiles of inhaled insoluble particles, (ii) particle size-dependent pharmacokinetics of inhaled monodisperse particles, (iii) pharmacokinetic differences between inhaled fluticasone propionate and budesonide, as well as (iv) pharmacokinetic differences between healthy volunteers and asthmatic patients. Finally, to identify the most impactful optimization criteria for orally inhaled drugs, the developed mechanistic model was applied to investigate the impact of input parameters on both the pulmonary and systemic exposure. Interestingly, the solubility of the inhaled drug did not have any relevant impact on the local and systemic pharmacokinetics. Instead, the pulmonary dissolution rate, the particle size, the tissue affinity, and the systemic clearance were the most impactful potential optimization parameters. In the future, the developed prediction framework should be considered a powerful tool for identifying optimal drug and formulation characteristics.     

Mechanistic prediction of food effects for Compound A tablet using PBPK model

Physiologically based pharmacokinetic (PBPK) modeling has been extensively used to study the factors of effect drug absorption, distribution, metabolize and extraction progress in human. In this study, Compound A(CPD A) is a BCS Class II drug, which has been extensive applied in clinical as lipid-lowering drug, administered orally after food, they displayed positive food effects in human, A PBPK model was built to mechanistic investigate the food effect of CPD A tablet in our study. By using gastroplus™ software, the PBPK models accurately predicted the results of food effects and predicted data were within 2-fold error of the observed results. The PBPK model mechanistic illuminated the changes of pharmacokinetic values for the positive food effects of the compound in human. Here in, the PBPK modeling which were combined with ACAT absorption models in it, successfully simulated the food effect in human of the drug. The simulation results were proved that PBPK model can be able to serve as a potential tool to predict the food effect on certain oral drugs.     

Single Cell Analysis of Drug Distribution by Intravital Imaging

Recent advances in the field of intravital imaging have for the first time allowed us to conduct pharmacokinetic and pharmacodynamic studies at the single cell level in live animal models. Due to these advances, there is now a critical need for automated analysis of pharmacokinetic data. To address this, we began by surveying common thresholding methods to determine which would be most appropriate for identifying fluorescently labeled drugs in intravital imaging. We then developed a segmentation algorithm that allows semi-automated analysis of pharmacokinetic data at the single cell level. Ultimately, we were able to show that drug concentrations can indeed be extracted from serial intravital imaging in an automated fashion. We believe that the application of this algorithm will be of value to the analysis of intravital microscopy imaging particularly when imaging drug action at the single cell level.     

Simulation of differential drug pharmacokinetics under heat and exercise stress using a physiologically based pharmacokinetic modeling approach

Under extreme conditions of heat exposure and exercise stress, the human body undergoes major physiological changes. Perturbations in organ blood flows, gastrointestinal properties, and vascular physiology may impact the body's ability to absorb, distribute, and eliminate drugs. Clinical studies on the effect of these stressors on drug pharmacokinetics demonstrate that the likelihood of pharmacokinetic alteration is dependent on drug properties and the intensity of the stressor. The objectives of this study were to use literature data to quantify the correlation between exercise and heat exposure intensity to changing physiological parameters and further, to use this information for the parameterization of a whole-body, physiologically based pharmacokinetic model for the purposes of determining those drug properties most likely to demonstrate altered drug pharmacokinetics under stress. Cardiac output and most organ blood flows were correlated with heart rate using regression analysis. Other altered parameters included hematocrit and intravascular albumin concentration. Pharmacokinetic simulations of intravenous and oral administration of hypothetical drugs with either a low or high value of lipophilicity, unbound fraction in plasma, and unbound intrinsic hepatic clearance demonstrated that the area under the curve of those drugs with a high unbound intrinsic clearance was most affected (up to a 130% increase) following intravenous administration, whereas following oral administration, pharmacokinetic changes were smaller (<40% increase in area under the curve) for all hypothetical compounds. A midazolam physiologically based pharmacokinetic model was also used to demonstrate that simulated changes in pharmacokinetic parameters under exercise and heat stress were generally consistent with those reported in the literature.     

Nanotechnology and pharmaceutical inhalation aerosols

Pharmaceutical inhalation aerosols have been playing a crucial role in the health and well being of millions of people throughout the world for many years. The technology's continual advancement, the ease of use and the more desirable pulmonary-rather-than-needle delivery for systemic drugs has increased the attraction for the pharmaceutical aerosol in recent years. But administration of drugs by the pulmonary route is technically challenging because oral deposition can be high, and variations in inhalation technique can affect the quantity of drug delivered to the lungs. Recent advances in nanotechnology, particularly drug delivery field have encouraged formulation scientists to expand their reach in solving tricky problems related to drug delivery. Moreover, application of nanotechnology to aerosol science has opened up a new category of pharmaceutical aerosols (collectively known as nanoenabled-aerosols) with added advantages and effectiveness. In this review, some of the latest approaches of nano-enabled aerosol drug delivery system (including nano-suspension, trojan particles, bioadhesive nanoparticles and smart particle aerosols) that can be employed successfully to overcome problems of conventional aerosol systems have been introduced.     

A quantitative model for metabolic intervention using gut microbes

As medicine shifts toward precision-based and personalized therapeutics, utilizing more complex biomolecules to treat increasingly difficult and rare conditions, microorganisms provide an avenue for realizing the production and processing necessary for novel drug pipelines. More so, probiotic microbes can be co-opted to deliver therapeutics by oral administration as living drugs, able to survive and safely transit the digestive tract. As living therapeutics are in their nascency, traditional pharmacokinetic–pharmacodynamic (PK–PD) models for evaluating drug candidates are not appropriate for this novel platform. Using a living therapeutic in late-stage clinical development for phenylketonuria (PKU) as a case study, we adapt traditional oral drug delivery models to properly evaluate and inform the engineering of living therapeutics. We develop the adapted for living therapeutics compartmental absorption and transit (ALT-CAT) model to provide metrics for drug efficacy across nine age groups of PKU patients and evaluate model parameters that are influenced by patient physiology, microbe selection and therapeutic production, and dosing formulations. In particular, the ALT-CAT model describes the mathematical framework to model the behavior of orally delivered engineered bacteria that act as living therapeutics by adapting similar methods that have been developed and widely-used for small molecular drug delivery and absorption.     

Targeting drug delivery to the lungs by inhalation

Most drugs targeted to the respiratory tract are used for their local action. For example, ephidrine for nasal decongestion, beta-2 agonists for bronchodilatation, and inhaled steroids to suppress the inflammation seen in asthmatic airways. Since the drug is delivered directly to its required site, only a small quantity is needed for an adequate therapeutic response, and consequently there is a low incidence of systemic side effects compared with oral or intravenous administration. More recently, it has become apparent that the lining of the respiratory tract, from nasal mucosa to airways and alveoli, may be used for the absorption of a drug for its systemic effect. This route of administration may be particularly attractive if it avoids the metabolic destruction encountered when some drugs are administered by alternative routes (for instance, peptides and proteins are rapidly destroyed by peptidases when Oven by the oral route). If there is a lack ofclinical response to an aerosolized drug, it is important to question whether the drug has failed or whether delivery to the site of action is inadequate. To deliver therapeutic agents by inhalation to the lower respiratory tract, inhaled drug particles must have appropriate aerodynamic characteristics. In addition, the anatomy and pathophysiology of the patient's respiratory tract, mode of inhalation through the inhaler, and the characteristics of the inhalational device itself, may significantly affect drug deposition.