, Washington, USA.
, Oregon, USA.
Pharm Res. 2024 Jun;41(6):1149-1161. doi: 10.1007/s11095-024-03707-0. Epub 2024 May 8.
The in vitro permeation test (IVPT) using ex vivo human skin is a sensitive and robust model system that has been vital in elucidating the fundamental parameters surrounding the absorption of both therapeutic agents and industrial chemicals through skin. FDA and OECD IVPT Guidances recommend that each skin section selected for study should be screened prior to use to ensure that the stratum corneum integrity is retained. Three methods are currently considered acceptable: 1) transepidermal water loss (TEWL), 2) electrical resistance, and 3) tritiated water (HO) absorption.
A retrospective analysis of data from the authors' laboratory has been performed with the objective of addressing a number of questions regarding the HO and TEWL integrity tests, and the population attributes of a large database consisting of 17,330 individual skin sections obtained from 459 skin donors. The applicability and usefulness of these tests, when compared to companion permeation data obtained from 25 topical drug products, has also been examined.
Both integrity tests found water permeability to be equal in White and Hispanic races but higher than in Blacks, HO being more discriminating than TEWL. Male skin is more permeable than female and there is a slight decrease in permeability with advancing age in both groups. Correlation between HO absorption and drug absorption revealed a minimal relationship between the two in most cases, the Pearson correlation coefficient ranging from -0.417 to 0.953. Additionally, drug outliers were not always identified with a failing integrity test.
The results call for a critical reexamination of the value of the HO integrity test, and by extension, TEWL, for use in IVPT studies.
使用离体人皮肤进行体外渗透试验（IVPT）是一种敏感且强大的模型系统，对于阐明治疗剂和工业化学品通过皮肤吸收的基本参数至关重要。FDA 和 OECD 的 IVPT 指南建议，在使用之前，应筛选每个用于研究的皮肤切片，以确保角质层完整性得以保留。目前有三种方法被认为是可接受的：1）经皮水分损失（TEWL），2）电阻，3）氚水（HO）吸收。
对作者实验室的数据进行了回顾性分析，目的是解决有关 HO 和 TEWL 完整性测试的许多问题，以及由 459 名供体获得的 17,330 个个体皮肤切片组成的大型数据库的人群属性。还检查了这些测试与 25 种局部药物产品获得的伴随渗透数据相比的适用性和有用性。
这两种完整性测试都发现白人和西班牙裔种族的水渗透性相等，但高于黑人，HO 比 TEWL 更具辨别力。男性皮肤比女性皮肤更具渗透性，并且在两个群体中，年龄增长都会导致渗透性略有下降。HO 吸收与药物吸收之间的相关性表明，在大多数情况下，两者之间的关系最小，皮尔逊相关系数范围从-0.417 到 0.953。此外，药物异常值并不总是通过完整性测试失败来识别。
结果呼吁对 HO 完整性测试的价值进行批判性重新评估，并且通过延伸，对 TEWL 在 IVPT 研究中的使用进行批判性重新评估。
