pH‐Dependent Partitioning of Acidic and Basic Drugs into Liposomes—A Quantitative Structure‐Activity Relationship Analysis

Klaus-Jürgen Schaper, Huabei Zhang, O. Raevsky
{"title":"pH‐Dependent Partitioning of Acidic and Basic Drugs into Liposomes—A Quantitative Structure‐Activity Relationship Analysis","authors":"Klaus-Jürgen Schaper, Huabei Zhang, O. Raevsky","doi":"10.1002/1521-3838(200105)20:1<46::AID-QSAR46>3.0.CO;2-X","DOIUrl":null,"url":null,"abstract":"The partitioning of drugs in the phospholipid liposome/water system has often been used as a model for the investigation of drug/cell membrane interactions. Generally distribution/pH profiles for acidic and basic compounds observed in the phospholipid/water system cannot be predicted by profiles obtained in the octanol/water system. This is true especially for pH regions where acids and bases are ionized. Based on the well-known pH-partition theory our nonlinear regression analysis of published pH-dependent liposome-water distribution coefficients of 18 basic and acidic drugs resulted in equations with satisfactory predictive power. Surprisingly the separate equations describing the partitioning of neutral, anionic or cationic drugs into phosphatidylcholine liposomes are rather similar with respect to significant physicochemical properties and their regression coefficients. Despite being differently charged the distribution of all three species into the phospholipid bilayer increases with size/bulk (polarizability α) and decreases with polarity characterized by the sum of substructural partial charges. Furthermore, for the neutral compounds and their cations an unfavorable effect of H-bond acceptor strength on distribution is found. Unexpectedly the H-bond donor effect of neutral or ionized species does not seem to influence their liposome partitioning behavior (as observed within each group of neutral, cationic or anionic drugs). Generally the distribution of ionizable molecules into phospholipid bilayers decreases with increasing degree of ionization. In this data set it was found for the first time that specific N-H-acidic drugs may show the opposite behavior. Obviously anions with a delocalized negative charge like anions of tautomeric pyrimidinones/pyrimidinols have the possibility to enter into some strong special interaction with phospholipid molecules.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2001-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"20","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Quantitative Structure-activity Relationships","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1002/1521-3838(200105)20:1<46::AID-QSAR46>3.0.CO;2-X","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 20

Abstract

The partitioning of drugs in the phospholipid liposome/water system has often been used as a model for the investigation of drug/cell membrane interactions. Generally distribution/pH profiles for acidic and basic compounds observed in the phospholipid/water system cannot be predicted by profiles obtained in the octanol/water system. This is true especially for pH regions where acids and bases are ionized. Based on the well-known pH-partition theory our nonlinear regression analysis of published pH-dependent liposome-water distribution coefficients of 18 basic and acidic drugs resulted in equations with satisfactory predictive power. Surprisingly the separate equations describing the partitioning of neutral, anionic or cationic drugs into phosphatidylcholine liposomes are rather similar with respect to significant physicochemical properties and their regression coefficients. Despite being differently charged the distribution of all three species into the phospholipid bilayer increases with size/bulk (polarizability α) and decreases with polarity characterized by the sum of substructural partial charges. Furthermore, for the neutral compounds and their cations an unfavorable effect of H-bond acceptor strength on distribution is found. Unexpectedly the H-bond donor effect of neutral or ionized species does not seem to influence their liposome partitioning behavior (as observed within each group of neutral, cationic or anionic drugs). Generally the distribution of ionizable molecules into phospholipid bilayers decreases with increasing degree of ionization. In this data set it was found for the first time that specific N-H-acidic drugs may show the opposite behavior. Obviously anions with a delocalized negative charge like anions of tautomeric pyrimidinones/pyrimidinols have the possibility to enter into some strong special interaction with phospholipid molecules.
酸性和碱性药物进入脂质体的pH依赖性分配-定量结构-活性关系分析
磷脂脂质体/水系统中药物的分配常被用作研究药物/细胞膜相互作用的模型。通常,在磷脂/水体系中观察到的酸性和碱性化合物的分布/pH分布不能通过在辛醇/水体系中获得的分布来预测。这对酸碱电离的pH区尤其适用。基于著名的ph分配理论,我们对已发表的18种碱性和酸性药物的ph依赖性脂质体-水分布系数进行了非线性回归分析,得到了具有满意预测能力的方程。令人惊讶的是,描述中性、阴离子或阳离子药物进入磷脂酰胆碱脂质体的单独方程在重要的物理化学性质和回归系数方面相当相似。尽管带不同的电荷,但这三种物质在磷脂双分子层中的分布随尺寸/体积(极化率α)的增加而增加,而随极性(亚结构部分电荷的总和)的减少而减少。此外,对于中性化合物及其阳离子,发现氢键受体强度对其分布有不利影响。出乎意料的是,中性或电离物质的氢键供体效应似乎并不影响它们的脂质体分配行为(在每组中性、阳离子或阴离子药物中观察到)。一般来说,可电离分子在磷脂双分子层中的分布随着电离程度的增加而减少。在这个数据集中,首次发现特定的n - h酸性药物可能表现出相反的行为。显然,带离域负电荷的阴离子,如互变异构嘧啶/嘧啶醇阴离子,有可能与磷脂分子发生某种强烈的特殊相互作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信