Effect of barrier perturbation on cutaneous salicylic acid penetration in human skin: in vivo pharmacokinetics using microdialysis and non‐invasive quantification of barrier function
Effect of barrier perturbation on cutaneous salicylic acid penetration in human skin: in vivo pharmacokinetics using microdialysis and non‐invasive quantification of barrier function
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DOI：
10.1046/j.1365-2133.1999.02859.x
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发表时间：
1999-04
影响因子：
10.3
通讯作者：
Benfeldt;Serup;Menné
中科院分区：
文献类型：
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作者：
Benfeldt;Serup;Menné
在左前臂掌侧敷贴后，我们使用真皮微透析法评估水杨酸(SA)在健康志愿者(n=18)中的渗透动力学。在四个部位监测渗透情况：正常(未修饰)皮肤和屏障功能受扰的皮肤(I)反复剥离胶带(Ii)1或2%十二烷基硫酸钠(SLS)作用24 h的刺激性皮炎和(Iii)丙酮脱脂。治疗的顺序按照拉丁方设计随机排列。使用蒸发法和比色法评估每个部位的表皮屏障功能和皮肤刺激性。经皮失水(TEWL)值证实，轻度(丙酮)、中度(1%SLS)和严重屏障损伤(胶带剥离和2%SLS)均已发生。在每个受试者的四个治疗区中的每一个区域，用两个平行的探头在真皮中进行微透析采样。将SA(5%乙醇)涂抹在贴附在皮肤上的微透析探头上，继续采样4h。SA在所有样本中均可检测到，并在所有透过扰动皮肤的样本中均可测量到。在相同受试者中，SA在屏障干扰皮肤和未修饰皮肤中的平均渗透率在丙酮处理的皮肤中分别增加了2.22倍(P=0.012)，在轻度皮炎中增加了46倍，在重度皮炎和胶带剥离皮肤中分别增加了146和157倍(P<；0.001)。SA的穿透率与TEWL(P=0.01)和红斑(P=0.02)的屏障干扰值显著相关。在丙酮处理的皮肤中，SA渗透的微透析采样比非侵入性测量技术更敏感地检测到显著的屏障干扰。随着SLS预处理浓度的增加和刺激性皮炎程度的增加，SA的经皮渗透呈正的剂量-反应关系。当按前臂上的位置分析数据时，发现对屏障损伤的反应性有区域内变化的趋势，对于相同的屏障扰动程序，最近的位置表现出比最远的位置更高的反应性分数。金黄色葡萄球菌在不同地区的渗透率无显著差异。综上所述，利用真皮微透析法获得靶器官的实时皮肤药代动力学，本研究证明SA在屏障干扰皮肤中的皮肤渗透率和差异性很高。测量的药物渗透被证明与屏障损伤的非侵入性量化相关。
We have used microdialysis in the dermis for assessing penetration kinetics of salicylic acid (SA) in healthy volunteers (n = 18), following application on the volar aspect of the left forearm. Penetration was monitored at four locations: in normal (unmodified) skin and in skin with perturbed barrier function from (i) repeated tape stripping (ii) irritant dermatitis from 1 or 2% sodium lauryl sulphate (SLS) for 24 h and (iii) delipidization by acetone. The order of the treatments was randomized according to a latin square design. Epidermal barrier function and skin irritation were assessed in each location using evaporimetry and colorimetry. Transepidermal water loss (TEWL) values confirmed that both mild (acetone), moderate (1% SLS) and severe barrier damage (tape stripping and 2% SLS) had occurred. Microdialysis sampling with two parallel probes in the dermis was performed in each of the four treatment areas for every subject. SA (5% in ethanol) was applied in a chamber glued to the skin overlying the microdialysis probes and sampling was continued for 4 h. SA was detectable in all samples and measurable in all samples from penetration through perturbed skin. Comparing the SA penetration in barrier‐perturbed skin with the penetration in unmodified skin in the same subject, the mean SA penetration increase was 2.2‐fold in acetone‐treated skin (P = 0.012), 46‐fold in mild dermatitis and 146‐ and 157‐fold in severe dermatitis and tape stripped skin, respectively (P < 0.001). The penetration of SA significantly correlated with the measurements of barrier perturbation by TEWL (P = 0.01) and erythema (P = 0.02) for each individual. Microdialysis sampling of SA penetration was more sensitive than non‐invasive measuring techniques in detecting significant barrier perturbation in acetone‐treated skin. A positive dose–response relationship for the percutaneous penetration of SA in response to increasing SLS pretreatment concentrations and thus the degree of irritant dermatitis was found. When analysing data by location on the forearm, a tendency towards an intraregional variation in the reactivity to barrier damage was found, with the most proximal location displaying higher reactivity scores than the most distal location in response to the same barrier perturbation procedures. The penetration of SA was not significantly different between locations. In conclusion, using microdialysis in the dermis to obtain real‐time dermal pharmacokinetics in the target organ, this study demonstrates highly increased and differentiated cutaneous penetration of SA in barrier‐perturbed skin. The measured drug penetration was demonstrated to correlate with non‐invasive quantification of barrier damage.