Metabolic approaches to enhance transdermal drug delivery. 1. Effect of lipid synthesis inhibitors.
Metabolic approaches to enhance transdermal drug delivery. 1. Effect of lipid synthesis inhibitors.
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DOI：
10.1021/js950219p
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发表时间：
1996-06
影响因子：
3.8
通讯作者：
Jui Chen Tsai;R. H. Guy;C. Thornfeldt;W. Gao;K. Feingold;K. Feingold;P. M. Elias;P. M. Elias
中科院分区：
文献类型：
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作者：
Jui Chen Tsai;R. H. Guy;C. Thornfeldt;W. Gao;K. Feingold;K. Feingold;P. M. Elias;P. M. Elias
含有胆固醇、游离脂肪酸和神经酰胺的混合物的角质层的细胞间结构域介导亲脂性和亲水性分子的表皮渗透屏障和透皮递送。先前的研究表明，三种关键脂质中的每一种都是正常屏障功能所必需的。例如，选择性抑制表皮中的胆固醇、脂肪酸或神经酰胺合成延迟了无毛小鼠皮肤体内屏障扰动后的屏障恢复速率。在这项研究中，我们研究了某些脂质合成抑制剂增强利多卡因或咖啡因透皮递送的潜力，因为它们能够扰乱屏障稳态。丙酮破坏屏障后，利多卡因释放的程度和屏障功能改变的程度相互矛盾。此外，由脂肪酸合成抑制剂5-（十四烷氧基）-2-呋喃羧酸（TOFA）、胆固醇合成抑制剂氟伐他汀（FLU）或胆固醇硫酸盐（CS）产生的屏障功能的进一步改变导致利多卡因吸收的进一步增加。此外，TOFA和CS的共同应用导致利多卡因摄取的累加增加。最后，当屏障最初用DMSO而不是丙酮破坏时，药物递送发生相当的增加; TOFA和FLU一起共同应用再次延迟屏障恢复，并使药物递送增加约8倍，与标准增强载体的递送相比。尽管这些代谢抑制剂也间接增加了所研究药物的辛醇/水分配（可能通过肤色或pH改变），但单独的抑制剂的物理化学作用并不改变完整皮肤中的药物摄取;即，被动机制本身不能解释药物输送的净增加。我们的研究结果表明，表皮脂质生物合成的调制，常规的，化学渗透增强剂的应用程序后，导致进一步提高药物输送，归因于这些代理商的能力，改变渗透屏障稳态和热力学。这种生物化学/代谢方法提供了一种新的手段，以提高透皮药物输送与化学增强剂的同时或先前使用。
The intercellular domains of the stratum corneum, which contain a mixture of cholesterol, free fatty acids, and ceramides, mediate both the epidermal permeability barrier and the transdermal delivery of both lipophilic and hydrophilic molecules. Prior studies have shown that each of the three key lipid classes is required for normal barrier function. For example, selective inhibition of either cholesterol, fatty acid, or ceramide synthesis in the epidermis delays barrier recovery rates after barrier perturbation of hairless mouse skin in vivo. In this study, we investigated the potential of certain inhibitors of lipid synthesis to enhance the transdermal delivery of lidocaine or caffeine as a result of their capacity to perturb barrier homeostasis. After acetone disruption of the barrier, the extent of lidocaine delivery and the degree of altered barrier function paralleled each other. Moreover, the further alteration in barrier function produced by either the fatty acid synthesis inhibitor 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), the cholesterol synthesis inhibitor fluvastatin (FLU), or cholesterol sulfate (CS) resulted in a further increase in lidocaine absorption. Furthermore, coapplications of TOFA and CS together caused an additive increase in lidocaine uptake. Finally, a comparable increase in drug delivery occurred when the barrier was disrupted initially with DMSO instead of acetone; coapplications of TOFA and FLU together again delayed barrier recovery and increased drug delivery by about 8-fold vs delivery from a standard enhancing vehicle. Whereas these metabolic inhibitors also variably increased the octanol/water partitioning of the drugs studied (perhaps via complexion or pH alterations), physicochemical effects of the inhibitors alone did not alter drug uptake in intact skin; i.e., passive mechanisms alone cannot account for the net increase in drug delivery. Our results show that modulations of epidermal lipid biosynthesis, following application of conventional, chemical penetration enhancers, cause a further boost in drug delivery, attributable to the ability of these agents to alter both permeability barrier homeostasis and thermodynamics. This biochemical/metabolic approach provides a novel means to enhance transdermal drug delivery in conjunction with the concurrent or prior use of chemical enhancers.