PERCUTANEOUS ABSORPTION AND METABOLISM IN HUMAN SKIN

人体皮肤的经皮吸收和代谢

• 批准号: 3456960
• 负责人: LYNN K PERSHING
• 金额: $ 10.17万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3456960
• 关键词: biopsy; cyclosporines; cytochrome P450; detoxification; diffusion; dosage; dosage forms; gastrointestinal absorption /transport; homeostasis; immunotoxicity; liver metabolism; skin; skin disorder; skin pharmacology; skin transplantation; toxicant interaction; unspecific monooxygenase; urinalysis

Percutaneous absorption of xenobiotics across skin is a process governed by diffusion, with the nonviable stratum corneum as the rate-limiting barrier. The epidermis and dermis are viable and contain the mixed function oxidase system (cytochrome P-450), which is responsible for the metabolism of hormones and detoxification of xenobiotics. The interaction of these two processes, simultaneous absorption and metabolism of compounds in the skin in vivo, are critical to understanding the pharmacological efficacy and fate of compounds topically applied. Although previous studies have investigated the influence of dose, hydration, stratum corneum thickness and vehicle on percutaneous absorption across human skin, there is a paucity of data concerning the influence of these parameters on skin metabolism and the interaction of these two processes in vivo. The human skin sandwich flap (HSSF) we developed is uniquely qualified to study absorption and metabolism in human skin, because the flap has intact functional, viable human skin, which is maintained by a biological support system with a single isolated, yet accessible artery and vein. Simultaneous absorption and metabolic events occurring in the skin can therefore be monitored by sampling blood from the vein immediately draining the area of skin on the flap exposed to drug. Local skin metabolism can be compared and contrasted with systemic events by analyzing local and systemic blood samples, urine, and skin biopsies. The broad objective of this proposal is to define the interactive processes of percutaneous absorption and metabolism of topically applied substances in skin. The proposed research focuses on experiments which are directed at two major hypotheses 1) the flap can be utilized for studying cutaneous metabolism and 2) physiological and physical parameters can be manipulated to alter cutaneous metabolism. Specific aims include the development of analytical techniques to identify and quantify cutaneous metabolism; comparison of skin and hepatic metabolism; comparison of metabolism in grafted and nongrafted skin; investigating the disposition of parent and metabolites in blood, urine and skin; study of the influence of dose, stratum corneum thickness, blood flow and cyclosporine on cutaneous metabolism. Understanding the interaction between absorption and metabolism processes in the skin are imperative to furthering our knowledge of skin pharmacology, homeostasis, protection from toxic compound exposure, bioequivalency and immunology of skin irritation and allergic reaction.

皮肤对异生物质的经皮吸收是一个由以下因素控制的过程： 扩散，以非活性角质层作为限速屏障。 表皮和真皮具有活性并含有混合功能氧化酶 系统（细胞色素 P-450），负责新陈代谢 激素和异生物质的解毒。 这两者的相互作用 皮肤中化合物的同时吸收和代谢过程 体内，对于了解药理功效和 局部应用的化合物的命运。 虽然之前的研究已经 研究了剂量、水合作用、角质层厚度的影响 和载体在人体皮肤上的经皮吸收，有一个 缺乏有关这些参数对皮肤影响的数据 体内代谢以及这两个过程的相互作用。 人类 我们开发的皮肤夹层皮瓣（HSSF）具有独特的研究资格 人体皮肤的吸收和代谢，因为皮瓣具有完整的 功能性的、有活力的人类皮肤，由生物支持物维持 具有单一隔离但可访问的动脉和静脉的系统。 皮肤中同时发生的吸收和代谢事件可以 因此可以通过立即引流的静脉采样血液来进行监测 皮瓣上暴露于药物的皮肤区域。 局部皮肤新陈代谢可以 通过分析局部和系统事件来进行比较和对比 全身血液样本、尿液和皮肤活检。 的广泛目标 该提案旨在定义经皮的交互过程 皮肤局部涂抹物质的吸收和代谢。 这 拟议的研究重点是针对两个主要领域的实验 假设1）皮瓣可用于研究皮肤代谢 2）可以操纵生理和物理参数来改变 皮肤代谢。 具体目标包括发展分析 识别和量化皮肤代谢的技术；比较 皮肤和肝脏代谢；嫁接和移植的代谢比较 非移植皮肤；研究母体和代谢物的处置 血液、尿液和皮肤；剂量、角质层影响的研究 厚度、血流量和环孢素对皮肤代谢的影响。 了解吸收和代谢过程之间的相互作用 对于加深我们对皮肤的了解至关重要 药理学、体内平衡、防止有毒化合物暴露、 皮肤刺激和过敏反应的生物等效性和免疫学。