磷脂膜色谱及其在生物药剂学中的应用

亲脂性参数在解释药物体内吸收、分布和排泄及预测生物活性等方面的重要性早已被人们认识。几种简单有机溶剂 水分配系统的模型都曾被用于评价药物的亲脂性 ,但其中取得较为成功的为正辛醇 水系统[1 ] 。在定量构效关系和药物合理设计上 ,它已成为标准疏水性参数 ,构成了药物特征参数的数据库。近年来 ,研究表明正辛醇 水系统并不能完全模拟所有类型药物在生物膜模型 (液晶态脂质体膜 )上的分配行为 ,导致其不能解释由不同化学结构类型药物组成集合的药动学和药效学特征。研究结果表明其分配系数与稳态下脑 血浓度比值或穿透血脑屏障渗透系数间无明显联系[2 ] 。这主要是因为各向同性、不带电荷中心的正辛醇相并不是呈液晶态生物膜上有序磷脂双分子层的客观模型。为了建立更精确的生物膜模拟系统 ,曾有文献[3]报道合成了磷脂膜界面 (ｉｍｍｏｂｉｌｉｚｅｄａｒｔｉｆｉｃｉａｌｍｅｍ ｂｒａｎｅ,ＩＡＭ) ,并将其作为固定相填料引入高效液相色谱系统 ,组成了磷脂膜色谱 (ＩＡＭｃｈｒｏｍａｔｏｇｒａｐｈｙ)。对结构相似的苯乙胺衍生物 ,磷脂膜色谱与正辛醇 水系统给出相似的亲脂性测量尺度 (ｒ =0 985 ) [4 ] ;但对于由不同化学...     

磷脂膜色谱用于评价药物与有序磷脂膜的相互作用磷脂膜色谱用于评价药物与有序磷脂膜的相互作用

目的使用磷脂膜色谱考察药物与有序磷脂膜的相互作用。方法使用磷脂膜色谱测定药物与有序磷脂膜的相互作用强度，表示为药物的膜亲和性参数(lg K_IAM)。使用正辛醇/水系统测定药物的疏水性参数(lg DO/W,7.4)。结果在有机调节剂百分比(φ) 0～30%范围内，容量因子对数值(lg K′_IAM)与φ呈现良好线性关系；对于3种有机调节剂(甲醇、乙醇和乙腈)，lg K′_IAM与φ间曲线截距相同，但斜率有显著差别。从对羟基苯甲酸甲酯到丁酯，每增加一个CH₂对测定的亲脂性参数差值(Δlg K_IAM和Δlg DO/W,7.4)具有相似的影响，但是从对羟基苯甲酸到甲酯的差值却明显偏离这个规律。结论磷脂膜色谱是一个简便、有效和快速的用于评价药物与有序磷脂膜相互作用的工具。     

通过喹诺酮抗生素与磷脂膜的相互作用预测肺泡巨噬细胞单层的体外摄取

目的;预测肺泡巨噬细胞单层的体外摄取.方法:以培养的肺泡巨噬细胞单层为体外模型,用磷脂膜色谱,脂质体/水系统评价药物与磷脂膜的相互作用,分别表示为lg k_(1AM),lg D_(L B,7.4),用正辛醇/水系统测定参考的疏水性参数(lg D_(O/B,7.4).结果:lg D_(L B,7.4)(r~2=0.93)比lg D_(O B,7.4)(r~2=0.65)具有与lg k_(1AM)更显著的相关性.lg k_(1AM)和lg D_(L B,7.4)均 比lg D_(O/B,7.4)与细胞内药物的蓄积度有更好的相关性.但对于由5个两性喹酮抗生素和奎尼丁组成的受试集合,三者均与药物进入细胞内的速度具有相近的显著的正相关性.结论:磷脂膜色谱和脂质体/水系统给出相似的亲脂性测量尺度,且均与正辛醇/水系统区别有显著性.与疏水性参数相比,膜亲和性是更有效的肺泡巨噬细胞内药物蓄积和结合的预测参数.     

两性分子与有序磷脂膜的相互作用模式

目的　揭示两性分子与有序磷脂膜的作用模式。方法　分别使用磷脂膜色谱和正辛醇 水系统测定药物的膜亲和性和疏水性参数。结果　两性分子与有序磷脂膜存在吸引性极性附加作用力 ,其测定的膜亲和性参数要明显比由疏水性参数预测的值高。结论　结合两性分子复杂的微观质子平衡 ,不仅其中性、阳性而且两性的微观离子可能通过匹配的构象和能量有利的作用模式而有效的分布到有序的两性磷脂膜中 ,并且后两者的分配产生了与有序磷脂膜的吸引性极性附加作用力     

自乳化药物传递系统的研究概况

目的:总结自乳化药物传递系统的研究概况.方法:对近期自乳化药物传递系统的形成机制、处方组成、体外质量评价及其在药剂学方面的应用进行介绍.结果与结论:自乳化药物传递系统对亲脂性和水难溶性的药物是一个非常有前景的新型载体系统.     

美国药物相互作用计算机审查系统的发展与应用概况

随着20世纪60年代以后计算机在美国医药卫生领域的广泛应用,运用药物治疗监测软件系统监测和指导临床用药成为保证并提高合理用药水平的有效途径之一。药物相互作用计算机审查系统作为其主要内容之一,取得了迅速的发展。从70年人中期到90年代初,在美国临床药学领域,已先后有HELP、MEDIPHOR、PADIS、Medicom Micro Plus、Medical Letter、S-O-A-P、Drug Interaction by Homsten、DTSS、RxTriage、Cross-Check等十几种具有药物相互作用审查功能的计算机软件系统成功研制和开发出来^[4,5]。并且,随着其功能的完善、应用模式的成熟和应用效益的提高,药物相互作用计算机审查系统在美国医药领域的应用日趋广泛。1996年美国医药领域调查表明,美国医院药房中拥有计算机系统的占92.7%,其中应用计算机系统监测药物相互作用的有62.4%^[6]。这些系统的广泛应用,对于提高美国临床合理用药的水平发挥了重要的作用。本文将就美国药物相互作用计算机审查系统的功能与性能要求、实际应用的效果及对其应用效益的评价作一综述。     

中国中药与日本汉方药喜结良缘 上海津村制药有限公司开工奠基

[本刊讯]由日本最大的汉方药生产企业津村株式会社与上海市药材有限公司、上海张江高科技园区开发股份公司合资组建的上海津村制药有限公司,３月２６日在上海张江高科技园区举行了     

环胍类:一种新型的抗血小板凝集剂:咪唑并[1,2-a]噻嗯并嘧啶-2-酮类衍生物

作者等注意到,在若干血小板凝集抑制剂中含有亲脂性的内酰胺结构。因而认为,内酰胺结构是化合物通过氢键与酶蛋白结合起作用所必须的基团,同时,化合物中的亲脂基团能增强相互作用。据此,作者合成一系列新的1,2,3,5-四氢咪唑并[1,2-a]噻嗯并[2,3-d],-     

平行人工膜渗透模型及其应用进展

随着新药研发水平的提高,每类药物的候选化合物增多,研究工作量明显增加,对化合物进行快速筛选的方法已经成为研究的重点之一。平行人工膜渗透模型(PAMPA)作为药物筛选的有力工具,已用于药物研究中。该模型主要以人工磷脂作为生物膜来模拟药物跨膜的屏障,用于药物的膜渗透研究。本文介绍了平行人工膜渗透模型的建立、特点和研究进展,概述了利用PAMPA进行药物筛选等方面内容。通过调整人工磷脂膜的配比,PAMPA能够作为肠道、血脑屏障和皮肤吸收等体外模型。作为药物被动转运模型,PAMPA能够对药物进行高通量快速筛选,具有成本低、灵活、用药量少和重现性好等特点。     

化学法—酶法靶向释药对分析工作的挑战

化学法-酶法靶向释药（化学递释系统和软药）新方法的发展，依赖于特异而灵敏的分析技术，HPLC已成为用来分离在体内外由于酶和（或）化学转化而在靶上产生的药物和复杂混合物组分的有力手段。欲使化学分离成功，需要色谱柱与溶质之间的相互作用具备专一性，以分离不同化学特性的化合物。在建立方法过程中应考虑的主要因素是组分的亲脂性、离子化或中性性质方面存在的差异，此外还必须经常改进对分析组分的专一性，以对从作用部位取得的组织样品提供适当的检测限。然而，色谱法的不足之处是不能对未知组分加以识别，质谱法不管作为直接鉴定技术还是与色谱联用，可能是解决问题的途径。本综述对这些问题及未来发展趋势进行了讨论。     

Toward an optimal blood-brain barrier shuttle by synthesis and evaluation of peptide libraries

Several peptide families containing N-methylated amino acids were designed and synthesized using solid-phase peptide synthesis (SPPS). The permeability and phospholipophilicity of these compounds were studied by parallel artificial membrane permeability assay (PAMPA) and immobilized artificial membrane chromatography (IAMC) to select the best peptides in terms of length, terminal groups, and amino acid replacement to be used as carriers that pass through a model of the blood-brain barrier (BBB) by passive diffusion. Furthermore, the enzymatic stability of these peptides in human serum and their cell viability by MTT assay were tested. These peptide families showed great stability and nontoxicity. The three peptides that showed the greatest permeability were coupled to levodopa (a nonpassive permeating drug) and assessed. These peptides effectively transferred levodopa through an artificial membrane by means of passive diffusion.     

Can protonated β-blockers interact with biomembranes stronger than neutral isolipophilic compounds?: A chromatographic study on three different phospholipid stationary phases (IAM-HPLC)

The chromatographic capacity factors (k′) of 10 β-adrenoceptor antagonists (“β-blockers”) were measured on three different immobilized artificial membrane-phosphatidylcholine (IAM-PC) HPLC stationary phases, namely IAM-PC-MG, IAM-PC-DD2, and IAM-PC-DD. The two former phases are made of phosphatidylcholine as found in biomembranes and differ each other in end-capping of free propylamino residues whereas the latter is made of single-chain phosphatidylcholine analogues. On IAM-PC-DD2 we found that structurally unrelated neutral compounds give a single correlation between log k′ values and the respective octanol/water partition coefficients (log P), as previously observed on IAM-PC-MG phase. This was not observed on the IAM-PC-DD phase. IAM chromatography was performed at a pH of the aqueous eluent (7.0) close to the physiological pH 7.4. Retention on all IAM phases showed a biphasic pattern, being proportional to log P^N (lipophilicity of neutral forms) for more lipophilic congeners (log P^N > 1.90), and quite constant for the others. The comparison of β-blocker retention with that of neutral compounds on IAM-PC-MG and IAM-PC-DD2 suggests that they can interact with phospholipids as strongly or more strongly than neutral isolipophilic compounds, despite their being more than 98% in their ionized form. Therefore, we hypothesize that electrostatic interactions play a pivotal role in the interactions between β-blockers and membrane phospholipids.     

Potential of immobilized artificial membrane chromatography for lipophilicity determination of arylpropionic acid non-steroidal anti-inflammatory drugs

Molecular lipophilicity can be expressed by logP or more conveniently by logk, i.e. determined by the traditional shake-flask technique or by liquid chromatography. The logk of 11 arylpropionic non-steroidal anti-inflammatory drugs (NSAIDs) was determined at pH 7.4 of the eluent using two stationary phases i.e. octadecylsilane phase and an immobilized artificial membrane (IAM.PC.MG) packing. The chromatographic retention factors extrapolated to 100% aqueous phase (logk(wODS) and logk(wIAM)) were correlated with n-octanol/water lipophilicity parameters (logP) and with n-octanol/water partition coefficients corrected for ionization at pH 7.4 (logD7.4). In this series of compounds, significant linear correlations (r>0.94) between the chromatographic parameters (logk(wIAM)) and the reference lipophilicity data (logP and logD7.4) were described. Moreover, regression analysis between the lipophilicity parameters and some pharmacokinetic data for the drugs under study were performed. The logk(wIAM) parameter over n-octanol/water partition data seems to provide a good model to obtain lipophilicity parameters of arylpropionic acid NSAIDs for quantitative structure-activity relationships studies.     

Liquid chromatographic retention of beta-adrenoceptor antagonists: an index of lipid solubility

The in-vitro lipophilicity of nine beta-adrenoceptor antagonists was evaluated based on retention on a reverse-phase C-18 high-pressure liquid chromatographic (hplc) system at physiologic pH. Propranolol was by far the most lipophilic drug, while atenolol and sotolol were the least. Hplc retention was highly correlated (r = 0.92) with octanol: buffer partition coefficient. Thus hplc retention is a rapid and replicable approach to the determination of in-vitro lipophilicity that does not require radioactive drug.     

The hydrophobic fragmental constant approach forcalculating log P in octanol/water and aliphatic hydrocarbon/water systems

We have investigated the relationship between drug retention in immobilized liposome partitioning chromatography and liposome partitioning and found a strong linear correlation. Separate linear relationships were found depending on the charge of the compound when liposome chromatographic measurements were related to the octanol/water partition coefficients. We have also investigated the importance of the water/octanol partition coefficient in quantitative structure–property relationships related to drug transport properties. The studies show that the inclusion of a parameter related to lipophilicity causes only, at best, a marginal increase in internal predictivity and, at worst, a decrease in external predictivity. The studies also show that parameters related to hydrogen bonding, polarizability and size are important properties that need to be included in quantitative models for drug transport processes. We believe that the use of multivariate characterizations of compounds based on non-composite parameters may result in better and more predictive models compared with models based on parameters of a more composite nature when investigating the possibilities to establish quantitative structure–property relationships. This revised version was published online in August 2006 with corrections to the Cover Date.