Therapeutics Research Centre, School of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, QLD 4120, Australia.
Br J Clin Pharmacol. 2012 Apr;73(4):564-78. doi: 10.1111/j.1365-2125.2011.04128.x.
Many products are applied to human skin for local effects in deeper tissues. Animal studies suggest that deep dermal and/or subcutaneous delivery may be facilitated by both dermal diffusion and transport via the cutaneous vasculature. However, the relationship between the extent and pathways of penetration, drug physicochemical properties and deeper tissue physiology is not well understood.
We have used a physiologically based pharmacokinetic model to analyze published human cutaneous microdialysis data, complemented by our own in vitro skin penetration studies. We found that convective blood, lymphatic and interstitial flow led to significant deep tissue concentrations for drugs that are highly plasma protein bound. In such cases, deeper tissue concentrations will occur earlier and may be several orders of magnitude greater than predicted by passive dermal diffusion alone.
To relate the varying dermal, subcutaneous and muscle microdialysate concentrations found in man after topical application to the nature of the drug applied and to the underlying physiology.
We developed a physiologically based pharmacokinetic model in which transport to deeper tissues was determined by tissue diffusion, blood, lymphatic and intersitial flow transport and drug properties. The model was applied to interpret published human microdialysis data, estimated in vitro dermal diffusion and protein binding affinity of drugs that have been previously applied topically in vivo and measured in deep cutaneous tissues over time.
Deeper tissue microdialysis concentrations for various drugs in vivo vary widely. Here, we show that carriage by the blood to the deeper tissues below topical application sites facilitates the transport of highly plasma protein bound drugs that penetrate the skin, leading to rapid and significant concentrations in those tissues. Hence, the fractional concentration for the highly plasma protein bound diclofenac in deeper tissues is 0.79 times that in a probe 4.5 mm below a superficial probe whereas the corresponding fractional concentration for the poorly protein bound nicotine is 0.02. Their corresponding estimated in vivo lag times for appearance of the drugs in the deeper probes were 1.1 min for diclofenac and 30 min for nicotine.
Poorly plasma protein bound drugs are mainly transported to deeper tissues after topical application by tissue diffusion whereas the transport of highly plasma protein bound drugs is additionally facilitated by convective blood, lymphatic and interstitial transport to deep tissues.
许多产品应用于人体皮肤，以在深层组织中发挥局部作用。动物研究表明，真皮扩散和通过皮肤脉管系统的运输都可能促进真皮的深层和/或皮下传递。然而，渗透的程度和途径、药物的物理化学性质和深层组织生理学之间的关系尚未得到很好的理解。
我们使用基于生理学的药代动力学模型来分析已发表的人体皮肤微透析数据，并辅以我们自己的体外皮肤渗透研究。我们发现，对于与血浆蛋白高度结合的药物，对流血液、淋巴和间质流导致深层组织中的药物浓度显著升高。在这种情况下，深层组织中的浓度会更早出现，并且可能比单独通过被动皮肤扩散预测的高几个数量级。
将人类经皮给药后在真皮、皮下和肌肉微透析液中发现的浓度变化与所应用药物的性质以及潜在的生理学联系起来。
我们开发了一种基于生理学的药代动力学模型，其中向深层组织的输送由组织扩散、血液、淋巴和间质流输送以及药物特性决定。该模型应用于解释已发表的人体微透析数据，这些数据是通过估计体外皮肤扩散和已在体内经皮应用的药物的蛋白结合亲和力而得出的，并在一段时间内测量了深部皮肤组织中的药物浓度。
各种药物在体内的深层组织微透析浓度差异很大。在这里，我们表明，血液携带至皮肤表面下的深层组织有助于高血浆蛋白结合药物的穿透皮肤，从而导致这些组织中快速而显著的浓度。因此，高度与血浆蛋白结合的双氯芬酸在深层组织中的分数浓度是浅探针下 4.5mm 处探针的 0.79 倍，而与之相比，低蛋白结合的尼古丁的分数浓度为 0.02。它们在较深探针中出现药物的估计体内滞后时间分别为双氯芬酸的 1.1 分钟和尼古丁的 30 分钟。
低血浆蛋白结合药物主要通过组织扩散在经皮给药后向深层组织转运，而高血浆蛋白结合药物的转运则通过对流血液、淋巴和间质向深层组织的运输得到额外促进。
