Wagner Bjoern, Fischer Holger, Kansy Manfred, Seelig Anna, Assmus Frauke
F. Hoffmann-La Roche Ltd., pRED, Pharma Research and Early Development, Pharmaceutical Research, Innovation Center Basel, CH-4070 Basel, Switzerland.
Biozentrum, University of Basel, Div. of Biophysical Chemistry, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.
Eur J Pharm Sci. 2015 Feb 20;68:68-77. doi: 10.1016/j.ejps.2014.12.009. Epub 2014 Dec 13.
Here we present a miniaturized assay, referred to as Carrier-Mediated Distribution System (CAMDIS) for fast and reliable measurement of octanol/water distribution coefficients, log D(oct). By introducing a filter support for octanol, phase separation from water is facilitated and the tendency of emulsion formation (emulsification) at the interface is reduced. A guideline for the best practice of CAMDIS is given, describing a strategy to manage drug adsorption at the filter-supported octanol/buffer interface. We validated the assay on a set of 52 structurally diverse drugs with known shake flask log D(oct) values. Excellent agreement with literature data (r(2) = 0.996, standard error of estimate, SEE = 0.111), high reproducibility (standard deviation, SD < 0.1 log D(oct) units), minimal sample consumption (10 μL of 100 μM DMSO stock solution) and a broad analytical range (log D(oct) range = -0.5 to 4.2) make CAMDIS a valuable tool for the high-throughput assessment of log D(oc)t.
在此，我们介绍一种小型化分析方法，称为载体介导分配系统（CAMDIS），用于快速、可靠地测量正辛醇/水分配系数log D(oct)。通过引入用于正辛醇的滤膜支持物，促进了与水的相分离，并降低了界面处形成乳液（乳化）的趋势。给出了CAMDIS最佳实践指南，描述了一种管理滤膜支持的正辛醇/缓冲液界面处药物吸附的策略。我们在一组52种结构多样、已知摇瓶log D(oct)值的药物上验证了该分析方法。与文献数据高度一致（r(2) = 0.996，估计标准误差，SEE = 0.111）、高重现性（标准偏差，SD < 0.1 log D(oct)单位）、最小样品消耗（10 μL的100 μM DMSO储备溶液）以及较宽的分析范围（log D(oct)范围 = -0.5至4.2），使得CAMDIS成为高通量评估log D(oc)t的有价值工具。
