Inacio R, Barlow D, Kong X, Keeble J, Jones S A
King's College London, Faculty of Life Sciences & Medicine, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
King's College London, Faculty of Life Sciences & Medicine, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
Eur J Pharm Biopharm. 2016 May;102:214-22. doi: 10.1016/j.ejpb.2016.03.002. Epub 2016 Mar 8.
Relatively little is known about how drug self-association influences absorption into the human body. This study presented two hydrophobic membranes with a series of solutions containing different types of tetracaine aggregates with the aim of understanding how the attributes of supramolecular aggregate formation influenced passive membrane transport. The data showed that aqueous solutions of the unprotonated form of tetracaine displayed a significantly higher (p<0.05) passive membrane transport compared to solutions with mixtures of the unprotonated and protonated drug microspecies (e.g. transport through the skin was 0.96±0.31μgcm(-2)min(-1) and 1.59±0.26μgcm(-2)min(-1) respectively). However, despite an enhanced rate of drug transport and a better membrane partitioning the unionised molecules showed a significantly longer (p<0.05) lag time to membrane penetration compared solutions rich in the ionised microspecies. Analytical characterisation of the solutions applied to the apical surface of the membranes in the transport studies showed that larger tetracaine aggregates with smaller surface charge gave rise to the longer lag times. These large aggregates demonstrated more extensive intermolecular bonding and therefore, it was suggest that it was the enhanced propensity of the unionised species to form tightly bound drug aggregates that caused the delay in the membrane penetration.
关于药物自缔合如何影响人体吸收的了解相对较少。本研究展示了两种疏水膜以及一系列含有不同类型丁卡因聚集体的溶液，目的是了解超分子聚集体形成的特性如何影响被动膜转运。数据表明，与含有未质子化和质子化药物微物种混合物的溶液相比，未质子化形式的丁卡因水溶液表现出显著更高（p<0.05）的被动膜转运（例如，经皮转运分别为0.96±0.31μg·cm⁻²·min⁻¹和1.59±0.26μg·cm⁻²·min⁻¹）。然而，尽管药物转运速率提高且膜分配更好，但与富含离子化微物种的溶液相比，未离子化分子显示出显著更长（p<0.05）的膜渗透滞后时间。在转运研究中应用于膜顶表面的溶液的分析表征表明，具有较小表面电荷的较大丁卡因聚集体导致了更长的滞后时间。这些大聚集体表现出更广泛的分子间键合，因此，有人认为正是未离子化物种形成紧密结合药物聚集体的倾向增强导致了膜渗透的延迟。
