细胞药代动力学研究进展

经典的药物代谢动力学理论是建立在血浆药物浓度测定的基础上,常难以真实有效地预测体内药物的药效。很多药物必须穿透多重生物屏障,与细胞内的靶点相结合才能发挥药效。因此药代动力学研究迫切需要从“宏观”的血浆药物浓度深入到“微观”的细胞/ 亚细胞水平。综述细胞药代动力学研究领域取得的进展,重点介绍细胞药代动力学理论的提出、技术体系的建立及其在药物研发、筛选、临床方面的应用。     

有关药物代谢动力学的几个基本概念

药物代谢动力学(简称药代动力学)是药物代谢与数学两者之间的边缘学科。它用数学方程式定量地描述药物在体内吸收、分布、结构转化和排泄等过程的动态变化。药代动力学的研究成果对指导新药设计、优选给药方案、改进药物剂型、提高药物疗效、延长作用时间或减小毒副作用等方面已发挥重大作用。本文扼要介绍药代动力学的基本概念和一些基本公式,希望有助于它的普及应用。     

辛伐他汀自微乳化胶囊的体内评价

目的:研究辛伐他汀(SV)自微乳化胶囊在比格犬体内的药代动力学。方法:采用HPLC法测定比格犬血浆药物浓度,与市售片比较,考察SV自微乳化胶囊的体内药代动力学。结果:药代动力学测定结果表明:与市售片比较,自微乳化胶囊血药浓度达峰时间提前、最高血药浓度增大,Tmax=1.41h,Cmax=46.22ng.mL-1,而市售片的Tmax=2.65h,Cmax=12.43ng.mL-1;AUC0-∞为市售片剂的227.5%。结论:自微乳化胶囊可以显著提高SV的体内吸收。     

磺胺类药物在正常与肾衰家兔体内的药代动力学参数测算

目的了解磺胺类药物在肾衰与正常家兔体内代谢规律,掌握药代动力学参数的计算方法及肾衰对磺胺类药物代谢的影响。方法在家兔耳缘静脉注入磺胺嘧啶(SD),不同时间抽取动脉血,90分钟时从膀胱取尿,利用分光光度法测定血药浓度,计算半衰期。结果磺胺类药物在家兔体内呈现二房室模型代谢动力学特点,且肾衰家兔半衰期明显大于正常家兔,尿中浓度明显低于正常家兔。结论急性肾衰使磺胺类药物消除减慢,延长半衰期。     

抗肿瘤药物脂质体研究

<正>化学工业出版社出版本书在介绍脂质体及其在抗肿瘤治疗领域的概况及进展的基础上,重点论述了作者在脂质体技术应用在抗肿瘤药物领域的基础研究成果。主要内容包括:脂质体概述;脂质体在抗肿瘤药物领域的最新研究成果、应用特点和研究现状;抗肿瘤药物脂质体的制备方法、稳定性研究和质量控制等内容,尤其是对鱼精蛋白凝聚法分离载药脂质体与游离药物的适用范围的探讨;抗肿瘤药物脂质体处方及工艺的优化、体外释药机制、不同粒径脂质体体内动力学以及体内组     

抗肿瘤药物脂质体研究

正化学工业出版社出版本书在介绍脂质体及其在抗肿瘤治疗领域的概况及进展的基础上,重点论述了作者在脂质体技术应用在抗肿瘤药物领域的基础研究成果。主要内容包括:脂质体概述;脂质体在抗肿瘤药物领域的最新研究成果、应用特点和研究现状;抗肿瘤药物脂质体的制备方法、稳定性研究和质量控制等内容,尤其是对鱼精蛋白凝聚法分离载药脂质体与游离药物的适用范围的探讨;抗肿瘤药物脂质体处方及工艺的优化、体外释药机制、不同粒径脂质体体内动力学以及体内组     

重组人血管内皮抑素在Beagle犬体内的药代动力学研究

研究重组人血管内皮抑素(rhEndostatin)静脉注射后在Beagle犬体内的药代动力学过程,为临床应用提供药代动力学数据。用酶联免疫吸附试验(ELISA)竞争法检测Beagle犬静脉注射rhEndostatin后不同时间的血药浓度,并将血药浓度-时间数据经计算机拟合,计算出相应参数。rhEndostatin静脉注射Beagle犬后,药物的分布半衰期平均为(0.34±0.04)h,消除半衰期为(16.5±1.6)h。血药浓度-时间曲线下面积(AUC)与剂量呈正相关,相关系数为0.999 9。血浆清除率(CLs)均值为(0.123±0.006)l/h,高、中、低剂量CLs基本相同。rhEndostatin在Beagle犬体内的药代动学过程基本符合线性药动学特征,血药浓度-时间曲线符合二房室模型。rhEndostatin在Beagle犬体内药代动力学过程的研究对其进一步开发具有指导价值。     

三唑类抗真菌新药泊沙康唑和伏立康唑简介

随着侵袭性真菌感染的发病率和死亡率逐年增多,新近问世的新型抗真菌药物也越来越多。新一代广谱三唑类抗真菌药物泊沙康唑和伏立康唑,在体内和体外均有较强的抗真菌活性,临床上用其来预防和治疗侵袭性真菌感染。两药具有共有的作用机制,在抗真菌活性、药物代谢及安全性方面有着各自特点。分子结构上泊沙康唑和伏立康唑优于原有药物伊曲康唑和氟康唑,从而具备更强、更广的抗菌谱。两药的研发和应用表明抗真菌药物研究正朝着高效、广谱、低毒的方向发展,成为治疗各种类型真菌感染新的有力手段。然而,两药在临床研究和血药浓度监测方面仍待深入探究。本文将从分子结构、作用机制、适应症和药代动力学方面介绍两药,并对两药在未来的临床应用进行展望,为临床应用提供帮助。     

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 …     

细胞的命运:间充质干细胞的药代动力学

细胞药物已成为药物研发中最新的领域之一。由于细胞药物具有增殖和自主趋化的能力,其体内药学特征与传统的小分子和大分子药物差异很大。目前,虽然细胞药物已经开始走向临床,但是对于细胞类药物进入体内之后的命运变化普遍缺乏认识。如果能够借助药代动力学理论,预测不同细胞药物的体内分布、代谢/排泄规律,进而在细胞药物进入机体之后的动态分布和细胞疗效之间建立关系,将有效提高细胞药物的临床疗效,降低风险,减少药物的相互作用。在该文中,我们以间充质干细胞(mesenchymal stem cell,MSC)为例,整理了现有的一些研究成果,试图对细胞药物的药代动力学和其药效、毒效的关系进行归纳,为今后进一步探索细胞药物在体内的命运奠定基础。     

Microalgae as bioreactors for bioplastic production

Being protein function a conformation-dependent issue, avoiding aggregation during production is a major challenge in biotechnological processes, what is often successfully addressed by convenient upstream, midstream or downstream approaches. Even when obtained in soluble forms, proteins tend to aggregate, especially if stored and manipulated at high concentrations, as is the case of protein drugs for human therapy. Post-production protein aggregation is then a major concern in the pharmaceutical industry, as protein stability, pharmacokinetics, bioavailability, immunogenicity and side effects are largely dependent on the extent of aggregates formation. Apart from acting at the formulation level, the recombinant nature of protein drugs allows intervening at upstream stages through protein engineering, to produce analogue protein versions with higher stability and enhanced therapeutic values.     

The extraordinary ligand binding properties of human serum albumin

Human serum albumin (HSA), the most prominent protein in plasma, binds different classes of ligands at multiple sites. HSA provides a depot for many compounds, affects pharmacokinetics of many drugs, holds some ligands in a strained orientation providing their metabolic modification, renders potential toxins harmless transporting them to disposal sites, accounts for most of the antioxidant capacity of human serum, and acts as a NO-carrier. The globular domain structural organization of monomeric HSA is at the root of its allosteric properties which are reminiscent of those of multimeric proteins. Here, structural, functional, biotechnological, and biomedical aspects of ligand binding to HSA are summarized.     

Human serum albumin: from bench to bedside

Human serum albumin (HSA), the most abundant protein in plasma, is a monomeric multi-domain macromolecule, representing the main determinant of plasma oncotic pressure and the main modulator of fluid distribution between body compartments. HSA displays an extraordinary ligand binding capacity, providing a depot and carrier for many endogenous and exogenous compounds. Indeed, HSA represents the main carrier for fatty acids, affects pharmacokinetics of many drugs, provides the metabolic modification of some ligands, renders potential toxins harmless, accounts for most of the anti-oxidant capacity of human plasma, and displays (pseudo-)enzymatic properties. HSA is a valuable biomarker of many diseases, including cancer, rheumatoid arthritis, ischemia, post-menopausal obesity, severe acute graft-versus-host disease, and diseases that need monitoring of the glycemic control. Moreover, HSA is widely used clinically to treat several diseases, including hypovolemia, shock, burns, surgical blood loss, trauma, hemorrhage, cardiopulmonary bypass, acute respiratory distress syndrome, hemodialysis, acute liver failure, chronic liver disease, nutrition support, resuscitation, and hypoalbuminemia. Recently, biotechnological applications of HSA, including implantable biomaterials, surgical adhesives and sealants, biochromatography, ligand trapping, and fusion proteins, have been reported. Here, genetic, biochemical, biomedical, and biotechnological aspects of HSA are reviewed.     

Guidelines for analytical method development and validation of biotechnological synthesis of drugs. Production of a hydroxyprogesterone as model

In connection with biotechnological synthesis of pharmaceutical drugs, validated methods for quantification of both product and substrate at different time intervals are essential for proper calculation of rate coefficients. In this field, there still exist no guidelines for analytical validation, unlike the situation in the bioanalytical field. Therefore, in this study the detailed guidelines by FDA for bioanalytical method validation were applied to a typical biotechnological process; the enzymatic synthesis of 9alpha-hydroxyprogesterone in E. coli using progesterone as substrate. The process liquid was extracted and analyzed using an HPLC-DAD system. The quality control (QC) samples of the product demonstrated excellent precision (C.V.<1.5%) and accuracy between 99.3 and 107%. The study showed that the recommendations and the validation terms for bioanalytical methods can be used also for biotechnological production, but with some important exceptions. The tolerances (C.V. values) of the validation terms should be much narrower; the internal standard (I.S.) must be present in the process liquid before the start of the process and must be much different in structure from the substrate (so as not to participate in the biotechnological process). In addition, the selectivity must be checked very frequently during the process due to the changes in the blank process liquid with time.     

Stereoselective pharmacokinetics of oxprenolol,propranolol, and verapamil: Species differences and influence of endotoxin

The influence of endotoxin-induced inflammation was studied on the pharmacokinetics of the enantiomers of the racemic drugs oxprenolol, propranolol, and verapamil in rabbits and dogs. Enantioselective pharmacokinetics were seen for oxprenolol and propranolol in the rabbit and for propranolol and verapamil in the dog. In the dog, the enantioselective differences in plasma concentrations are due to differences in both protein binding and metabolism, whereas in the rabbit the differences are due solely to differences in metabolism. In both species endotoxin treatment increases the plasma concentrations of the enantiomers of the three drugs; both protein binding and metabolism are influenced. In rabbits and in dogs, the influence of endotoxin on the disposition of the three drugs is less enantioselective than was previously observed in the rat. © 1995 Wiley-Liss, Inc.     

Enzymatic biocatalysis in chemical synthesis of pharmaceuticals (Review)

In this review we summarize the available research on enzymatic biocatalysis in the chemical synthesis of drugs. We focus on oxydoreductsases, particularly ketoreductases, that are widely used in biotechnological processes: alpha- and omega-transaminases, lipases, nitrile hydrolases, and aldolases. The potential for the extended use of novel enzymes produced via bioengineering is discussed.     

Pharmacokinetics of non-steroidal anti-inflammatory drugs in male rabbits after acute and chronic administration and effect of chronic treatment on seminal prostaglandins, sperm quality and fertility

The pharmacokinetics of various non-steroidal anti-inflammatory drugs were determined to find dosage regimens by which drug concentrations known as active from human anti-inflammatory therapy could be reached and maintained in rabbits during continued administration. Based on the pharmacokinetics and side-effects of the different drugs, phenylbutazone was selected for the fertility experiments. Treatment of male rabbits with phenylbutazone for 9 consecutive days significantly reduced seminal concentrations of PGE-2 and PGF-2 alpha and tended to increase ejaculate volumes, sperm motility, and fertility. These results indicate that, at least in rabbits, inhibition of PG synthesis by prolonged treatment with non-steroidal anti-inflammatory drugs does not impair male fertility. Instead, chronic treatment with the drugs at non-toxic doses may improve sperm quality and fertility.     

Stereoselective determination and pharmacokinetics of dihydropyridines: an updated review

All dihydropyridines, except nifedipine, have at least one chiral center, and their pharmacokinetics and clinical effects differ from one enantiomer to another. Chiral separation methods for dihydropyridines using chromatographic techniques are discussed. The stereoselective pharmacokinetics of dihydropyridine calcium antagonists were reviewed in detail in 1995. The present review article updates the methods for the stereoselective determination of dihydropyridines using chromatographic techniques and summarizes the pharmacokinetics of the dihydropyridines, including the newest drugs under development.     

Biotechnological production and applications of Cordyceps militaris,a valued traditional Chinese medicine

Cordyceps militaris is a potential harborer of biometabolites for herbal drugs. For a long time, C. militaris has gained considerable significance in several clinical and biotechnological applications. Much knowledge has been gathered with regard to the C. militaris's importance in the genetic resources, nutritional and environmental requirements, mating behavior and biochemical pharmacological properties. The complete genome of C. militaris has recently been sequenced. This fungus has been the subject of many reviews, but few have focused on its biotechnological production of bioactive constituents. This mini-review focuses on the recent advances in the biotechnological production of bioactive compositions of C. militaris and the latest advances on novel applications from this laboratory and many others.