Cutaneous metabolism of nitroglycerin in vitro. II. Effects of skin condition and penetration enhancement.
Cutaneous metabolism of nitroglycerin in vitro. II. Effects of skin condition and penetration enhancement.
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硝酸甘油的体外皮肤代谢。
DOI：
10.1023/a:1015822431178
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发表时间：
1992
影响因子：
3.7
通讯作者：
Guy,RH
中科院分区：
文献类型：
--
作者：
Higo,N;Hinz,RS;Lau,DT;Benet,LZ;Guy,RH
本文用无毛小鼠离体皮肤研究了皮肤贮存、皮肤准备、透皮促进剂预处理和胶带剥离去除皮肤屏障对硝酸甘油（GTN）经皮转运和代谢的影响。在4°C下储存皮肤10天不会改变对总硝酸盐通量的屏障功能[GTN +1，2-甘油二硝酸酯（1，2-GDN）+1，3-甘油二硝酸酯（1，3-GDN）]。然而，代谢功能显著受损，并提示酶活性至少损失五倍。将皮肤加热至100°C持续5分钟明显损害无毛小鼠皮肤屏障功能。然而，水解GTN的能力仍然存在，并且在10小时的实验期间保持恒定，与“对照”相反，其显示出随时间推移酶功能逐渐降低。用1-十二烷基氮杂环庚烷-2-酮（Azone）（一种假定的渗透促进剂）对无毛小鼠皮肤进行体内预处理（在动物处死、组织切除和体外转运/代谢研究之前），显著降低了皮肤对硝酸盐通量的屏障（相对于适当的对照）。同样，屏障扰动导致在观察期间基本恒定的代谢活性。通过Azone处理，形成的代谢物的比率（1，2-GDN/1，3-GDN）从小于1增加到略高于1。胶带剥离通过去除角质层逐渐破坏皮肤屏障功能。15个胶带条的效果与Azone预处理的效果相同：大大增强的通量，10小时内代谢物形成的恒定百分比（再次），以及1，2-GDN/1，3 GDN比率的增加。总体而言，实验警告说，对于易受皮肤代谢影响的经皮药物递送候选物，屏障功能的状态（增强剂预处理、皮肤损伤或疾病等）可能会严重影响系统可用性。
The effects of skin storage, skin preparation, skin pretreatment with a penetration enhancer, and skin barrier removal by adhesive tape-stripping on the concurrent cutaneous transport and metabolism of nitroglycerin (GTN) have been studiedin vitrousing hairless mouse skin. Storing the skin for 10 days at 4°C did not alter barrier function to total nitrate flux [GTN + 1,2-glyceryl dinitrate (1,2-GDN) + 1,3-glyceryl dinitrate (1,3-GDN)]. However, metabolic function was significantly impaired and suggested at least fivefold loss of enzyme activity. Heating skin to 100°C for 5 min appreciably damaged hairless mouse skin barrier function. The ability to hydrolyze GTN was still present, however, and remained constant over the 10-hr experimental period, in contrast to the “control,” which showed progressively decreasing enzymatic function with time. Pretreatment of hairless mouse skinin vivo(prior to animal sacrifice, tissue excision, andin vitrotransport/metabolism studies) with 1-dodecylazacyclo-heptan-2-one (Azone), a putative penetration enhancer, significantly lowered the skin barrier to nitrate flux (relative to the appropriate control). Again, barrier perturbation resulted in essentially constant metabolic activity over the observation period. The ratio of metabolites formed (1,2-GDN/1,3-GDN) was increased from less than unity to slightly above 1 by the Azone treatment. Adhesive tape-stripping gradually destroyed skin barrier function by removal of the stratum corneum. The effects of 15 tape-strips were identical to those of Azone pretreatment: a greatly enhanced flux, a constant percentage formation of metabolites over 10 hr (once again), and an increase in the 1,2-GDN/1,3 GDN ratio. Overall, the experiments caution that, for transdermal drug delivery candidates susceptible to skin metabolism, the status of barrier function (enhancer pretreated, skin damage or disease, etc.) may significantly affect systemic availability.