芳樟醇对十八甲基炔诺酮经皮渗透对映体选择性的影响  

The potential effects of linalool on enantioselective skin permeation of norgestrel

作　　者：荣毅[1] 俞文英[1] 郭霞[1] 曾珊珊[1] 沈正荣[1] 曾苏[2] 叶金翠[1] 

机构地区：[1]浙江省医学科学院药物研究所,浙江杭州310013 [2]浙江大学药学院,浙江杭州310006

出　　处：《药学学报》2014年第8期1175-1180,共6页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(30901871);省部共建项目(201231507);浙江省科技厅项目(2011C13003;2014F10034;2012F10005);浙江省医学重点学科群建设资助项目(XKQ-010-001);浙江省卫生高层次创新人才培养工程项目

摘　　要：本文以十八甲基炔诺酮(norgestrel,NG)为手性模型药物,研究其经离体大鼠皮肤渗透的对映体选择性以及手性促透剂芳樟醇和皮肤类脂对NG经皮渗透对映体选择性的影响。采用Valia-Chien双室渗透池进行离体皮肤渗透实验,手性HPLC法检测渗透液样品,考察了NG经完整皮肤和去类脂皮肤渗透的对映体选择性及芳樟醇的影响。结果表明,当dl-NG或l-NG于无水乙醇-水(2∶8,v/v)饱和溶液中,未观察到dl-NG经皮渗透的对映体选择性,但dl-NG的皮肤渗透速率是l-NG的2倍,这主要归因于l-NG和dl-NG间溶解度的差异;当加入dl-芳樟醇后,dl-NG出现对映体选择性渗透,l-NG的稳态渗透速率高出d-NG 22%,而采用去类脂的皮肤进行相同实验时对映体选择性现象消失;傅里叶变换红外光谱检测显示,经dl-芳樟醇处理的皮肤角质层类脂的亚甲基不对称伸缩振动在波数上与对照组相比发生了蓝移。结果提示,dl-芳樟醇引起dl-NG对映体选择性经皮渗透与其对皮肤类脂的作用有关。皮肤类脂50%以上由手性物质神经酰胺组成,推测手性促透剂芳樟醇、皮肤类脂手性物质神经酰胺和/或手性药物NG之间可能存在对映体选择性相互作用。The purpose of this study is to investigate the enantioselectivity of norgestrel （biG） transdermal permeation and the potential influence of linalool and lipids on the enantioselectivity. In vitro skin permeation studies of NG across the excised rat skins were performed with Valia-Chien diffusion cells, and the permeation samples were analyzed by enantioselective HPLC. intact rat back skin and lipids extracted rat back skin The possible enantioselective permeation of NG across and the influence of linalool were evaluated. The skin permeation rate of dl-NG was two times higher than that of I-NG when donor solutions （EtOH/H20 2 ： 8, v/v） containing l-NG or dl-NG. It may be mainly attributed to the solubility discrepancy between enantiomer and racemate. The enantioselective permeation of dl-NG across intact rat skin was observed when the donor solutions containing dl-linalool. The permeation flux of l-NG was 22% higher than that of d-NG. But interestingly, the enantioselective permeation of dl-NG disappeared under the same experimental condition except that the lipid extracted rat skin was used. Attenuated total reflection-fourier transform infrared spectroscopy analysis of stratum corneum showed that the wave number for asymmetric CHz stretching vibrations of lipidstreated with dl-linalool was greater than that of the control. The results indicated that the enantioselective permeation of NG may be contributed by the interaction between dl-linalool and lipids. More than half of lipids were composed of ceramides. The stereospecific interaction maybe existed among chiral enhancer （linalool）, lipids （ceramides） and/or chiral drugs （NG）.

关 键 词：十八甲基炔诺酮 芳樟醇 对映体选择性 经皮给药 

分 类 号：R943[医药卫生—药剂学]