Jacques C, Perdu E, Jamin E L, Cravedi J P, Mavon A, Duplan H, Zalko D
INRA, Toxalim (Research Center in Food Toxicology), Université de Toulouse, Toulouse, France.
Skin Pharmacol Physiol. 2014;27(4):188. doi: 10.1159/000351683. Epub 2014 Mar 15.
The skin is a metabolically active organ expressing biotransformation enzymes able to metabolize both endogenous molecules and xenobiotics. We investigated the impact of metabolism on the delivery of testosterone through the skin with an ex vivo pig ear skin system as an alternative model for human skin. Penetration, absorption and metabolic capabilities were investigated up to 72 h after application of [(14)C]-testosterone doses of 50-800 nmol on either fresh or frozen skin, with the latter model being metabolically inactive. Testosterone absorption and metabolite production were monitored by radio-HPLC and gas chromatography-mass spectrometry. Testosterone absorption through frozen skin was much lower, irrespective of the dose of testosterone applied, compared to fresh skin. Using fresh skin samples, >95% of the radioactivity recovered in culture media, as well as the skin itself, corresponded to metabolites. These results were compared with the metabolic data obtained from other in vitro systems (liver and skin microsomes). The present work leads to the conclusion that most of the enzymatic activities expressed in liver fractions are also expressed in pig and human skin. The metabolic activity of the skin can modulate the biological activity of pharmaceuticals (and xenobiotics). Consequently, it can also greatly affect transdermal drug delivery.
皮肤是一个具有代谢活性的器官，表达能够代谢内源性分子和外源性物质的生物转化酶。我们用离体猪耳皮肤系统作为人类皮肤的替代模型，研究了代谢对睾酮经皮递送的影响。在新鲜或冷冻皮肤上涂抹50 - 800 nmol的[(14)C] - 睾酮剂量后72小时内，研究了其渗透、吸收和代谢能力，后者模型代谢无活性。通过放射性高效液相色谱和气相色谱 - 质谱法监测睾酮的吸收和代谢产物的产生。与新鲜皮肤相比，无论涂抹的睾酮剂量如何，冷冻皮肤对睾酮的吸收都要低得多。使用新鲜皮肤样本时，在培养基以及皮肤本身中回收的放射性物质中，>95%对应于代谢产物。这些结果与从其他体外系统（肝脏和皮肤微粒体）获得的代谢数据进行了比较。目前的工作得出结论，肝脏组分中表达的大多数酶活性在猪和人类皮肤中也有表达。皮肤的代谢活性可以调节药物（和外源性物质）的生物活性。因此，它也会极大地影响经皮给药。
