PERCUTANEOUS ABSORPTION AND METABOLISM IN HUMAN SKIN

人体皮肤的经皮吸收和代谢

基本信息

批准号：
2079410
负责人：
LYNN K PERSHING
金额：
$ 11.05万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-12-01 至 1994-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2079410
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

项目摘要

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.

皮肤上异种生物的经皮吸收是由扩散，无法生存的角膜作为限速屏障。表皮和真皮很可行，并包含混合功能氧化酶系统（细胞色素P-450），这是负责的代谢激素和异种生物的排毒。这两个的相互作用皮肤中化合物的过程，同时吸收和代谢在体内，对于理解药理功效和局部应用化合物的命运。尽管以前的研究有研究了剂量，水合，角质层厚度的影响和车辆在人体皮肤上的经皮吸收时，有一个关于这些参数对皮肤的影响的数据很少代谢和体内这两个过程的相互作用。人类我们开发的皮肤三明治皮瓣（HSSF）具有独特的资格来研究人类皮肤的吸收和代谢，因为皮瓣完好无损功能性，可行的人皮肤，由生物学支持维持具有单个孤立但易于接近的动脉和静脉的系统。皮肤中同时出现的吸收和代谢事件可以因此，通过从静脉立即抽水的血液采样来监测皮瓣上皮肤面积暴露于药物的区域。当地的皮肤代谢可以是通过分析本地和全身血液样本，尿液和皮肤活检。广泛的目标该建议是定义经皮的互动过程皮肤中局部应用物质的吸收和代谢。这拟议的研究重点是针对两个主要的实验假设1）可以将皮瓣用于研究皮肤代谢 2）可以操纵生理和物理参数以改变皮肤代谢。具体目的包括开发分析识别和量化皮肤代谢的技术；比较皮肤和肝代谢；嫁接和新陈代谢的比较非皮肤；调查父母和代谢物的处置血液，尿液和皮肤；研究剂量，角质层的影响皮肤代谢的厚度，血流和环孢菌素。了解吸收和代谢过程之间的相互作用在皮肤中，必须促进我们对皮肤的了解药理学，体内平衡，防止有毒复合暴露，皮肤刺激和过敏反应的生物等效性和免疫学。