Structural determinants of drug partitioning in n-hexadecane/water system.
Structural determinants of drug partitioning in n-hexadecane/water system.
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DOI：
10.1021/ci400112k
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发表时间：
2013-06-24
影响因子：
5.6
通讯作者：
Balaz S
中科院分区：
文献类型：
--
作者：
Natesan S;Wang Z;Lukacova V;Peng M;Subramaniam R;Lynch S;Balaz S
替代物相已被广泛用作模拟药物在生物系统中的转运和分配的相关物，利用替代物和磷脂双层之间的化学相似性作为生物相的基本单元，其负责大部分的转运和分配。磷脂双分子层中的溶剂化是一种重要的药物特性，因为它影响吸收和分布速率，以及与具有位于双分子层内的结合位点的膜蛋白的相互作用。双层核心可以由正十六烷（C16）模拟，并且由于高水含量，头基层通常被认为是亲水相。因此，我们测试的假设，C16/水分配系数（P）可以预测药物和其他小分子的双层位置比其他替代系统。从文献中收集或在必要时测量了不可电离（458）和完全电离（56）化合物的共514个PC 16/W值。为了创建基于片段的预测系统，基于ClogP片段化方案，将PC 16/W值分解为片段溶剂化参数（f）和校正因子。提供了使用ClogP输出进行PC 16/W预测的脚本。为了进一步扩展预测系统并揭示溶剂化差异，使用溶剂化显色参数将fC 16/W值与1-辛醇/水体系（O/W）中更广泛使用的对应物相关联。对具有已知双层位置的50种化合物的分析表明，单独的可用和预测的PC 16/W和PO/W值或代表它们的比率的PC 16/O值不能令人满意地预测药物在双层层中累积的偏好。这些观察结果表明，头基地层，虽然水合良好，不具有类似于水的溶剂化特性，也不好描述的O/W分区特性。
Surrogate phases have been widely used as correlates for modeling transport and partitioning of drugs in biological systems, taking advantage of chemical similarity between the surrogate and the phospholipid bilayer as the elementary unit of biological phases, which is responsible for most of transport and partitioning. Solvation in strata of the phospholipid bilayer is an important drug characteristics because it affects the rates of absorption and distribution, as well as the interactions with the membrane proteins having the binding sites located inside the bilayer. The bilayer core can be emulated by n-hexadecane (C16), and the headgroup stratum is often considered a hydrophilic phase because of the high water content. Therefore, we tested the hypothesis that the C16/water partition coefficients (P) can predict the bilayer locations of drugs and other small molecules better than other surrogate systems. Altogether 514 PC16/W values for nonionizable (458) and completely ionized (56) compounds were collected from the literature or measured, when necessary. With the intent to create a fragment-based prediction system, the PC16/W values were factorized into the fragment solvation parameters (f) and correction factors based on the ClogP fragmentation scheme. A script for the PC16/W prediction using the ClogP output is provided. To further expand the prediction system and reveal solvation differences, the fC16/W values were correlated with their more widely available counterparts for the 1-octanol/water system (O/W) using solvatochromic parameters. The analysis for 50 compounds with known bilayer location shows that the available and predicted PC16/W and PO/W values alone or the PC16/O values representing their ratio do not satisfactorily predict the preference for drug accumulation in bilayer strata. These observations indicate that the headgroups stratum, albeit well hydrated, does not have solvation characteristics similar to water and is also poorly described by the O/W partition characteristics.
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影响因子：
3.8
作者：
Abraham, Michael H.;Acree, William E., Jr.;Cavanaugh, Joseph E.
通讯作者：
Cavanaugh, Joseph E.
DOI：
10.1039/p29920002155
发表时间：
1992-12-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2
影响因子：
--
作者：
DALLAS, AJ;CARR, PW
通讯作者：
CARR, PW
影响因子：
2.9
作者：
BARRY, JA;GAWRISCH, K
通讯作者：
GAWRISCH, K
影响因子：
3.4
作者：
Balgavy, P;Dubnicková, M;Uhriková, D
通讯作者：
Uhriková, D
影响因子：
3.6
作者：
Abraham, MH;Platts, JA
通讯作者：
Platts, JA