药学学报, 2014, 49(8): 1175-1180
引用本文:
荣毅, 俞文英, 郭霞, 曾珊珊, 沈正荣, 曾苏, 叶金翠. 芳樟醇对十八甲基炔诺酮经皮渗透对映体选择性的影响[J]. 药学学报, 2014, 49(8): 1175-1180.
RONG Yi, YU Wen-ying, GUO Xia, ZENG Shan-shan, SHEN Zheng-rong, ZENG Su, YE Jin-cui. The potential effects of linalool on enantioselective skin permeation of norgestrel[J]. Acta Pharmaceutica Sinica, 2014, 49(8): 1175-1180.

芳樟醇对十八甲基炔诺酮经皮渗透对映体选择性的影响
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
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
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。
关键词:    十八甲基炔诺酮      芳樟醇      对映体选择性      经皮给药     
The potential effects of linalool on enantioselective skin permeation of norgestrel
RONG Yi1, YU Wen-ying1, GUO Xia1, ZENG Shan-shan1, SHEN Zheng-rong1, ZENG Su2, YE Jin-cui1
1. Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China;
2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310006, China
Abstract:
The purpose of this study is to investigate the enantioselectivity of norgestrel (NG) 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. The possible enantioselective permeation of NG across intact rat back skin and lipids extracted rat back skin and the influence of linalool were evaluated. The skin permeation rate of dl-NG was two times higher than that of l-NG when donor solutions (EtOH/H2O 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 CH2 stretching vibrations of lipids treated 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).
Key words:    norgestrel    linalool    enantioselectivity    transdermal administration   
收稿日期: 2014-03-13
基金项目: 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.
通讯作者: 叶金翠 Tel/Fax:86-571-88215573,E-mail:yejincui@163.com
Email: yejincui@163.com
相关功能
PDF(889KB) Free
打印本文
0
作者相关文章
荣毅  在本刊中的所有文章
俞文英  在本刊中的所有文章
郭霞  在本刊中的所有文章
曾珊珊  在本刊中的所有文章
沈正荣  在本刊中的所有文章
曾苏  在本刊中的所有文章
叶金翠  在本刊中的所有文章

参考文献:
[1] Kessner D, Ruettinger A, Kiselev MA, et al. Properties of ceramides and their impact on the stratum corneum structure [J]. Skin Pharmacol Physiol, 2008, 21: 58-74.
[2] Kommuru TR, Khan MA, Reddy IK. Effect of chiral enhancers on the permeability of optically active and racemic metoprolol across hairless mouse skin [J]. Chirality, 1999, 11: 536-540.
[3] Miyazaki K, Kaiho F, Inagaki A, et al. Enantiomeric differ-ence in percutaneous penetration of propranolol through rat excised skin [J]. Chem Pharm Bull, 1992, 40: 1075-1076.
[4] Zhu QG, Hu JH, Zeng HW. Stereoselectivity of skin carboxylesterase metabolism [J]. Acta Pharm Sin (药学学报), 2005, 40: 322-326.
[5] Conjeevaram R, Chaturvedula A, Betageri GV, et al. Ionto-phoretic in vivo transdermal delivery of β-blockers in hair-less rats and reduced skin irritation by liposomal formulation [J]. Pharm Res, 2003, 20: 1496-1501.
[6] Jones RC, Singer AC, Edgren RA. The biological activities of norgestrel and its enantiomers [J]. Int J Fertil, 1979, 24: 39-43.
[7] Jain S, Sapre R, Umamaheswari RB, et al. Protransfer-somes for effective transdermal delivery of norgestrel preparation and in vitro characterization [J]. Indian J Pharm Sci, 2003, 65: 152-160.
[8] Cui Y, Li LZ, Zhang L, et al. Enhancement and mecha-nism of transdermal absorption of terpene-induced propranolol hydrochloride [J]. Arch Pharm Res, 2011, 34: 1477-1485.
[9] Boncheva M, Damien F, Normand V. Molecular organiza-tion of the lipid matrix in intact Stratum corneum using ATR-FTIR spectroscopy [J]. Biochim Biophys Acta, 2008, 1778: 1344-1355.
[10] Obata Y, Utsumi S, Watanabe H, et al. Infrared spectro-scopic study of lipid interaction in stratum corneum treated with transdermal absorption enhancers [J]. Int J Pharm, 2010, 389: 18-23.
[11] Ye JC, Chen GS, Zeng S. Enantiomeric separation of norgestrel by reversed phase high-performance liquid chromatography using eluents containing hydroxypro-pyl-beta-cyclodextrin in stereoselective skin permeation study [J]. J Chromatogr B, 2006, 843: 289-294.
[12] van Smeden J, Hoppel L, van der Heijden R, et al. LC/MS analysis of stratum corneum lipids: ceramide profiling and discovery [J]. J Lipid Res, 2011, 52: 1211-1221.
[13] Yuan X, Capomacchia AC. Influence of physicochemical properties on the in vitro skin permeation of the enantiomers, racemate, and eutectics of ibuprofen for enhanced transdermal drug delivery [J]. J Pharm Sci, 2013, 102: 1957-1969.
[14] Kommuru TR, Khan MA, Reddy IK. Racemate and enantiomers of ketoprofen: phase diagram, thermodynamic studies, skin permeability, and use of chiral permeation enhancers [J]. J Pharm Sci, 1998, 87: 833-840.
[15] Vaddi HK, Ho PC, Chan YW, et al. Terpenes in ethanol: haloperidol permeation and partition through human skin and stratum corneum changes [J]. J Control Release, 2002, 81: 121-133.
[16] Heard CM, Brain KR. Does solute stereochemistry influ-ence percutaneous penetration? [J]. Chirality, 1995, 7: 305-309.