聚乙二醇修饰对重组人促红细胞生成素在大鼠体内药代动力学的影响

目的:研究聚乙二醇修饰对重组人促红细胞生成素在大鼠体内药代动力学的影响。方法:大鼠随机分成3组,分别单次皮下注射5μg·kg-1氨基葡萄糖-聚乙二醇-EPO(G-PEG-EPO)、甲氧基-聚乙二醇-EPO(M-PEG-EPO)和未经修饰的EPO原液后采集血样,采用酶联免疫吸附分析(ELISA)测定大鼠血浆样品中的EPO浓度。结果:给药后,与EPO相比,M-PEG-EPO,G-PEG-EPO较EPO吸收过程缓慢,峰浓度Cmax水平显著降低,代谢清除相对缓慢,末端消除相半衰期t1/2明显延长。而M-PEG-EPO,G-PEG-EPO的药代动力学参数除AUC0～inf和Cls外均无统计学差异。结论:聚乙二醇修饰能显著延长EPO在大鼠的末端消除相半衰期,G-PEG-EPO和M-PEG-EPO在大鼠的药代动力学性质相似。     

聚乙二醇化重组人生长激素在大鼠体内的药代动力学研究

用¹²⁵I标记示踪法研究大鼠皮下注射聚乙二醇化重组人生长激素（PEG-rhGH）药代动力学特征。大鼠sc PEG-rhGH后,测定血清PEG-rhGH浓度,用3P97程序拟和分析并计算药代动力学参数。大鼠sc PEG-rhGH 150、300或600 μg·kg^-1后,药物消除符合一房室模型。经与相关文献比较可知,生长激素经PEG化修饰后能延长其在体内的作用时间,达到长效目的。
     

蛋白质和多肽类药物修饰用聚乙二醇衍生物

聚乙二醇(PEG)修饰技术已成为改善蛋白质和多肽类药物临床疗效的重要手段。药物的PEG修饰研究,特别在提高蛋白质、多肽类药物的稳定性、延长半衰期(t_(1/2))等方面,具有持续的魅力和非常广阔的前景。近年,国内外药物PEG修饰技术研究主要集中在:增强PEG和蛋白质连接基团的稳定性;PEG新型衍生物的开发等。     

修饰蚯蚓纤溶酶的药代动力学研究

环毛蚓纤溶酶经聚乙二醇（PEG）和β-环糊精（β-CD）修饰后，分别静脉注射到猪体内和兔体内进行药代动力学研究。结果表明PEG-EFE在猪体内的半衰期为0.96h，而原酶在猪体内的半衰期为0.59h，PEG-EFE较原酶提高了1.62倍。β-CD-EFE注射于兔体内的药代动力学证明，β-CD-EFE在兔体内的分布相半衰期为1.00h，而原酶仅为0.65h，β-CD-EFE较原酶的体内半衰期提高了1.52倍。说明2种修饰方法都是有效的。     

基于第三代头孢菌素药动学相关研究的可视化分析

目的 梳理Web of Science数据库中关于第三代头孢菌素药动学(Pharmacokinetics, PK)研究,通过文献计量学和可视化分析方法,评价该领域的研究方向、研究热点以及发展趋势,为今后研究提供经验和借鉴。方法 使用Web of Science数据库进行检索,检索式为“Theme=("Third-Generation Cephalosporin"OR Cefoperazone) OR Ceftazidime) OR Cefixime) OR Cefodizime) OR Ceftriaxone) OR Cefotaxime) AND (pharmacokinetics OR PK OR"Population pharmacokinetics")”,检索时间为2009-2020年。利用VOS-viewer软件进行合著分析(作者、机构、国家)、共现分析和共引分析;通过GraphPadPrism8软件进行第三代头孢菌素药动学研究的趋势分析。结果 对纳入的818篇文献进行可视化分析,结果显示发文量呈现逐年上涨趋势,其中发文量最多的国家是美国(288篇,35.21%),最多的期刊...     

ELISA法研究聚乙二醇重组人生长激素注射液单次给药人体药代动力学

目的 建立ELISA方法研究聚乙二醇重组人生长激素(PEG-rhGH)注射液单次给药人体药代动力学.方法 将30名健康受试者随机分成4组(其中两组为自身对照),分别单次皮下注射PEG-rhGH注射液(0.1 mg·kg-1、0.2 mg·kg-1、0.4 mg·kg-1)、注射用重组人生长激素(rhGH)(0.067mg· kg-1).ELISA法测定不同时间点PEG-rhGH、rhGH的血药浓度,并计算药代动力学参数.结果 PEG-rhGH、rhGH血药浓度分别在0.312 5～40.0000 ng·ml-1、0.312 5～10.0000 ng· ml-1范围内线性关系良好,最低检测性均为0.312 5ng· ml-1,批间、批内RSD均＜15％. PEG-rhGH(0.1、0.2、0.4 mg·kg-1)、rhGH(0.067mg· kg-1)的t1/2分别为:(31.70±4.70)h、(32.19±4.58)h、(30.39±5.93)h、(1.95±0.44)h,Tmax为:(22.20±9.82)h、(29.40±10.75)h、(40.80±8.39)h、(3.20±1.10)h,Cmax:(105.24±45.37)ng·ml-1、(379.09±109.61)ng·m1-1、(920.69±293.21)ng·ml-1、(30.17±3.20)ng·m1-1,CL/F:(26.97±13.86) ml· kg-1· h-1、(9.21±4.05) ml· kg-1· h-1、(6.29±2.87) ml· kg-1· h-1、(284.26±43.47)ml· kg-1· h-1,AUC0→∞:(4657.70±2337.30) ng· m1-1·h、(25279.58±9407.63) ng· ml-1·h、(74438.89±29 007.81) ng·ml-1·h、(240.97±39.40) ng·ml-1·h.结论 PEG-rhGH体内过程符合线性动力学特征,与rhGH相比,明显推迟达峰时间、延长半衰期、减慢清除率,具有长效特征.     

蛋白质多肽类药物药代动力学及分析方法的研究进展

蛋白质多肽类药物,因生理活性强、疗效高而日益受到重视。为了正确评价蛋白质多肽类药物的疗效及安全性,必须研究其在动物和人体内的吸收、分布、代谢和排泄的规律。蛋白多肽类药物在实现商品化过程中,受到诸多因素的制约,而药物动力学的研究面临更严重的挑战。与小分子药物相比,蛋白多肽类药物具有相对分子质量大、不易透过生物膜、易在体内酶解、降解代谢途径多样等特点,因而在生物体内的药代动力学机制有其特殊性和复杂性。而且生物体内有大量相似物质的干扰,且该类药用量很小,大大增加了检测难度。笔者就对该类药物药代动力学特点及分析…     

奥沙利铂聚乙二醇修饰脂质体的制备及其大鼠体内的药动学

采用逆相蒸发-挤出法制备奥沙利铂聚乙二醇(PEG)修饰脂质体,处方中蛋黄卵磷脂E80-胆固醇-聚乙二醇修饰二硬脂酰磷脂酰乙醇胺(PEG 2000-DSPE)重量比为100∶25∶34,药脂比为1∶10.所得制品平均粒径为140 nm,包封率97.5％.采用HPLC法测定大鼠血浆中的奥沙利铂,考察奥沙利铂PEG修饰脂质体静注给予大鼠的药动学情况,并与奥沙利铂溶液相比较.结果显示,奥沙利铂PEG修饰脂质体组的cmax和AUC均显著大于溶液组(P＜0.05);平均滞留时间(MRT)比溶液组延长了约20倍.说明奥沙利铂PEG修饰脂质体能延长药物在大鼠体内的循环时间.     

群体药代动力学及其在新药研究中的应用

近年来新药临床研究越来越重视群体药代动力学的应用。群体药代动力学可以定量地描述病理、生理、合并用药等多种因素对药物代谢的影响，可将PK参数中的各种变异区分开，指导用药方案的调整，从而增强对新药有效性和安全性的评价。本文对群体药代动力学的研究方法及其在新药研究中的应用进行综述．     

蛋白质多肽类药物药代动力学研究的方法学和实验设计

评价了放射性同位素标记结合高效液相色谱法或电泳法研究生物活性蛋白质或多肽的药代动力学，并与免疫分析法和生物检定法进行比较. 结合本实验室对8个生物活性蛋白质或多肽研究中的经验着重评价了方法的特异性, 灵敏度, 精密度, 回收率和线性范围. 另外还探讨了药代动力学研究实验设计中某些重要问题.     

A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics

A mathematical pharmacokinetic/anti-drug-antibody (PK/ADA) model was constructed for quantitatively assessing immunogenicity for therapeutic proteins. The model is inspired by traditional pharmacokinetic/pharmacodynamic (PK/PD) models, and is based on the observed impact of ADA on protein drug clearance. The hypothesis for this work is that altered drug PK contains information about the extent and timing of ADA generation. By fitting drug PK profiles while accounting for ADA-mediated drug clearance, the model provides an approach to characterize ADA generation during the study, including the maximum ADA response, sensitivity of ADA response to drug dose level, affinity maturation rate, time lag to observe an ADA response, and the elimination rate for ADA–drug complex. The model also provides a mean to estimate putative concentration–time profiles for ADA, ADA–drug complex, and ADA binding affinity-time profile. When simulating ADA responses to various drug dose levels, bell-shaped dose–response curves were generated. The model contains simultaneous quantitative modeling and provides estimation of the characteristics of therapeutic protein drug PK and ADA responses in vivo. With further experimental validation, the model may be applied to the simulation of ADA response to therapeutic protein drugs in silico, or be applied in subsequent PK/PD models.     

辛伐他汀在老年高血脂患者中的群体药动学研究

目的：考察老年高血脂患者口服辛伐他汀的药动学模型,为临床制订个体化给药方案提供参考。方法：以30例服用辛伐他汀降血脂的老年高血脂患者为研究对象,于服药前与服药后20、62d3个时间点采血,以高效液相色谱（HPLC）法测定血药浓度,以生化法测定肌酐（Cr）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）等实验室检查指标;运用非线性混合效应模型（NONMEM）建立辛伐他汀的药动学模型;考察年龄、体重、肌酐清除率（CLcr）、ALT和AST等对药动学参数的影响,并以Bootstrap法进行模型验证。结果：本研究建立了口服辛伐他汀一级吸收和消除的一房室群体药动学模型;年龄、体重、CLcr等因素加入模型之后,基本模型并未改变（P〉0.05）。辛伐他汀表观清除率和表观分布容积的群体典型值分别为1020L·h-1和2350L。结论：本研究建立了老年高血脂患者口服辛伐他汀的群体药动学模型,为临床合理使用该药提供了依据。     

Design and Power of A Population Pharmacokinetic Study

Purpose. This paper investigated the influence of critical design factors on the power of a population pharmacokinetic (PK) study for identifying subpopulations that have different drug clearance than the typical population.Methods. A study simulation approach was used for the power estimation. The design factors included the number of subjects, sampling scheme, and compliance.Results. The false positive rates of incorrectly identifying a subpopulation were estimated for several scenarios. The false positive rates of the population PK study was relatively low, except when the numbers of subjects with full profiles and the subjects with troughs were distributed between populations in an unbalanced manner. The total number of subjects did not seem to have as much influence on study power as the number of subjects in the subpopulation, as long as the total number of subjects was significantly larger than the subpopulation. The variability of sampling time played an important role in both the statistical power and the accuracy of the estimated difference in clearance. Taking three samples provided greater power and better accuracy than taking two samples per subject. Taking only trough samples provided little power and poor estimation of clearance difference. Adding subjects with full profiles to a study with only trough samples taken in other subjects did not satisfactorily improve the clearance estimation. It was critical to account for dosing record in the population PK analysis to achieve appropriate power and accuracy. If the variability in dosing time was accounted for in the analysis, it improved the accuracy of the estimated difference in clearance. Missing dose administrations reduced the study power and resulted in deviation of estimated clearance difference.Conclusions. The power of a study should be determined prospectively to ensure appropriate study design for specific study objectives.     

The Influence of Protein Binding on the Pharmacokinetics of Sulphadimethoxine in Rabbits

Abstract The pharmacokinetics of sulphadimethoxine was investigated in rabbits at five dose levels. A significant nonlinearity of dose dependent pharmacokinetics was demonstrated. A large dose dependent change in per cent of sulphadimethoxine bound to plasma proteins was shown. It is concluded that the nonlinearity of the pharmacokinetics of sulphadimethoxine is mainly caused by the dose dependent changes in per cent of drug bound to plasma proteins.     

Allometric Pharmacokinetic Scaling: Towards the Prediction of Human Oral Pharmacokinetics

Purpose. To evaluate (1) allometric scaling of systemic clearance (CL)using unbound drug concentration, (2) the potential usage of brainweight (BRW) correction in allometric scaling of both CL and oralclearance (CL/F). Methods. Human clearance was predicted allometrically (CLu = a ·W^biv) using unbound plasma concentration for eight Parke-Daviscompounds and 29 drugs from literature sources. When the exponent b_ivwas higher than 0.85, BRW was incorporated into the allometricrelationship (CLu*BRW = a · W^biv). This approach was also applied tothe prediction of CLu/F for 10 Parke-Davis compounds. Human oralt1/2, Cmax, AUC, and bioavailability were estimated based onallometrically predicted pharmacokinetic (PK) parameters. Results. Human CL and CL/F were more accurately estimated usingunbound drug concentration and the prediction was further improvedwhen BRW was incorporated into the allometric relationship. ForParke-Davis compounds, the predicted human CL and CL/F werewithin 50-200% and 50-220% of the actual values, respectively. Theestimated human oral t1/2, Cmax, and AUC were within 82-220%,56-240%, and 73-190% of the actual values for all 7 compounds,suggesting that human oral PK parameters of those drugs could bereasonably predicted from animal data. Conclusions. Results from the retrospective analysis indicate thatallometric scaling of free concentration could be applied to orallyadministered drugs to gain knowledge of drug disposition in man, and to helpdecision-making at early stages of drug development.     

齐墩果酸对氟伐他汀在大鼠体内药动学的影响

目的 探讨齐墩果酸对氟伐他汀在大鼠体内的药代动力学影响。方法 将16只健康大鼠随机分为单药组(5.0mg?kg-1 氟伐他汀)和联合用药组(5.0mg?kg-1氟伐他汀 60mg?kg-1 齐墩果酸),单药组和联合用药组分别灌胃空白溶剂和齐墩果酸5天,每天一次。第6天两组均给予氟伐他汀灌胃,给药后不同时间点采血,LC-MS法测定大鼠体内血药浓度,比较两组间主要的药代动力学参数。结果 与单药组比较,联合用药组氟伐他汀主要药代动力学参数Cmax、AUC0-t参数值显著上升,组间比较差异具有统计学意义(P＜0.05)。结论 联合应用齐墩果酸可能影响大鼠体内氟伐他汀的药代动力学特性。     

利福喷丁对氨茶碱药代动力学的影响

本文应用紫外分光光度法对两组家兔分别单服氨茶碱及氨茶碱加服利福喷丁后的药代动力学参数进行了对比。结果表明,按8mg/kg的剂量连服利福喷丁4d可使氨茶碱的消除速率常数(K)升高;半衰期(t_(1/2))下降;曲线下面积(AUC)减小。经统计学处理p<0.05。提示在临床上两药同服时,应加强对氨茶碱的血药浓度监测,进行个体化给药以控制氨茶碱的有效血药浓度。     

The Effect of Amiodarone on Theophylline Pharmacokinetics in the Rat

Amiodarone is an investigational antiarrhythmic agent which has been implicated in reducing the activity of the hepatic mixed-function oxidase system. To evaluate this effect further, two groups of six male Sprague–Dawley rats each received theophylline (6 mg/kg, iv) preceded by either normal saline or amiodarone HC1 (100 mg/kg, iv). Blood samples were obtained serially for a period of 6 hr and the sera were assayed for theophylline by high-pressure liquid chromatography (HPLC). In rats pretreated with amiodarone, a significant 45% reduction in the mean (± SD) systemic clearance [0.057 (0.010) vs 0.031 (0.004) liter/hr/kg, P < 0.001] and a greater than 100% increase in the mean elimination half-life [2.03 (0.46) vs 4.29 (0.71) hr, P < 0.001] of theophylline were observed. These data demonstrate an acute inhibitory effect of amiodarone on the hepatic microsomal enzyme system.     

肾移植患者西罗莫司的群体药动学研究

目的:建立中国肾移植患者西罗莫司的群体药动学模型,为实施个体化用药提供理论支持。方法:选择47名肾移植术后采用西罗莫司+泼尼松+环孢素或他克莫司或霉酚酸酯(MMF)三联免疫抑制治疗的患者为研究对象,回顾性收集47名患者服药后的101个西罗莫司稳态血药浓度及相应的试验室检查数据,运用Winnonmix药动学软件,采用非线性混合效应模型(NONMEM)分析体重、年龄、性别、给药剂量、合并用药、肌酐清除率等对药动学参数的影响。最终模型的验证采用Jackknife法进行内部验证。结果:西罗莫司符合无滞后时间的一级消除动力学一室模型。固定效应结果量子,合用MMF和体重可影响药物清除率。最终模型公式为:CL/F(L·h-1)=11.01×0.14MMF+0.089×W。CL/F和Vd/F的群体典型值分别是11.01L·h-1和3616L,个体间变异分别为62.82%和85.07%。观测值和预测值间的残差(SD)和相关系数(r)分别是1.0ng·mL-1和0.94。结论:所建立的群体药动学模型能较好地估算服用西罗莫司的肾移植患者的个体及群体药动学参数,对指导临床个体化用药具有重要意义。     

氧氟沙星注射液治疗细菌性感染和药代动力学研究

国产氧氟沙星注射液治疗172例细菌感染性疾病,临床有效率和细菌阴转率均超过90％。和对照组诺氟沙星相比,无显著差异。169株细菌纸片法药敏试验表明,铜绿假单胞菌和其它假单胞菌20％耐药(6/30),大肠杆菌21.6％耐药(11/51)。药物副反应9.4％。测定3种不同给药途径血药浓度,口服和静脉组和文献报告一致,肌注后药浓度偏低。