Lai P M, Roberts M S
Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.
Pharm Res. 1998 Oct;15(10):1579-88. doi: 10.1023/a:1011959217935.
An in vitro study was carried out to determine the iontophoretic permeability of local anesthetics through human epidermis. The relationship between physicochemical structure and the permeability of these solutes was then examined using an ionic mobility-pore model developed to define quantitative relationships.
The iontophoretic permeability of both ester-type anesthetics (procaine, butacaine, tetracaine) and amide-type anesthetics (prilocaine, mepivacaine, lidocaine, bupivacaine, etidocaine, cinchocaine) were determined through excised human epidermis over 2 hrs using a constant d.c. current and Ag/AgCl electrodes. Individual ion mobilities were determined from conductivity measurements in aqueous solutions. Multiple stepwise regression was applied to interrelate the iontophoretic permeability of the solutes with their physical properties to examine the appropriateness of the ionic mobility-pore model and to determine the best predictor of iontophoretic permeability of the local anesthetics.
The logarithm of the iontophoretic permeability coefficient (log PC(j,iont)) for local anesthetics was directly related to the log ionic mobility and MW for the free volume form of the model when other conditions are held constant. Multiple linear regressions confirmed that log PC(j,iont) was best defined by ionic mobility (and its determinants: conductivity, pKa and MW) and MW.
Our results suggest that of the properties studied, the best predictors of iontophoretic transport of local anesthetics are ionic mobility (or pKa) and molecular size. These predictions are consistent with the ionic mobility pore model determined by the mobility of ions in the aqueous solution, the total current, epidermal permselectivity and other factors as defined by the model.
开展一项体外研究以测定局部麻醉药经人表皮的离子导入通透性。然后使用为定义定量关系而开发的离子迁移率 - 孔隙模型来研究这些溶质的物理化学结构与通透性之间的关系。
使用恒定直流电和银/氯化银电极，在2小时内测定酯类麻醉药（普鲁卡因、布他卡因、丁卡因）和酰胺类麻醉药（丙胺卡因、甲哌卡因、利多卡因、布比卡因、依替卡因、辛可卡因）经离体人表皮的离子导入通透性。通过水溶液中的电导率测量确定各个离子的迁移率。应用多元逐步回归将溶质的离子导入通透性与其物理性质相互关联，以检验离子迁移率 - 孔隙模型的适用性，并确定局部麻醉药离子导入通透性的最佳预测指标。
当其他条件保持恒定时，局部麻醉药的离子导入通透系数的对数（log PC(j,iont)）与模型自由体积形式的对数离子迁移率和分子量直接相关。多元线性回归证实，log PC(j,iont) 最好由离子迁移率（及其决定因素：电导率、pKa和分子量）和分子量来定义。
我们的结果表明，在所研究的性质中，局部麻醉药离子导入转运的最佳预测指标是离子迁移率（或pKa）和分子大小。这些预测与由水溶液中离子的迁移率、总电流、表皮选择通透性以及模型所定义的其他因素所确定的离子迁移率孔隙模型一致。
