Measurement of drug lipophilicity and pKa using acoustics.
Measurement of drug lipophilicity and pKa using acoustics.
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DOI：
10.1021/ac300087z
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发表时间：
2012-03
影响因子：
7.4
通讯作者：
Xin Li;M. Cooper
中科院分区：
文献类型：
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作者：
Xin Li;M. Cooper
化学品和候选药物的亲脂性通常描述在辛醇/水分配和log P方面。我们研究了一种替代的亲脂性测定方法，使用模拟的烷基醇与化合物分配使用声学传感定量。在压电声传感器的平面金电极上形成了由HSC（10）（CH（2）CH（2）O）（6）C（18）组成的自组装单分子膜。用覆盖log D值的4-log范围的化合物对系统进行挑战。作为化合物分配在界面层中，传感器谐振频率的变化被发现与化合物分配系数（log P）和分配系数（log D）。在不同pH值（pH 5.2至7.8）的水和生物缓冲液中，log（-dF/M（w）t）和log P以及log D之间建立了线性一致性（R（2）= 0.933）。反过来，药物pK（a）可以通过分析pH滴定期间的log D变化来确定。弱碱性药物（奎宁; pK（a）= 7.95）的亲脂性/pH曲线相对于-dF/M（w）值呈S形，其曲线与弱酸性药物（萘普生; pK（a）= 4.15）的曲线相反。
Lipophilicity of chemicals and drug candidates is normally described in terms of octanol/water partitioning and log P. We investigated an alternate approach to lipophilicity determination using a mimic of an alkyl alcohol with compound partitioning quantified using acoustic sensing. A self-assembled monolayer composed of HSC(10)(CH(2)CH(2)O)(6)C(18) was formed on planar gold electrodes of a piezoelectric acoustic sensor. The system was challenged with compounds covering a 4-log range of log D values. As compounds partitioned in the interfacial layer, changes in sensor resonant frequency were found to correlate with compound partition coefficients (log P) and with distribution coefficients (log D). Linear concordance (R(2) = 0.933) was established between log(-dF/M(w)t) and log P and with log D in both water and biological buffers at variant pH (pH 5.2 to 7.8). In turn, drug pK(a) could be determined by profiling log D changes during pH titration. The lipophilicity/pH profile of a weakly basic drug (quinine; pK(a) = 7.95) was sigmoidal with respect to -dF/M(w) values, with a profile inverse to that of a weakly acidic drug (naproxen; pK(a) = 4.15).