微透析法研究酮康唑经正常大鼠和糖尿病大鼠皮肤透过性的差异

The skin permeability difference of ketoconazole between normal rats and diabetic rats by microdialysis

目的研究酮康唑凝胶经正常大鼠和糖尿病大鼠皮肤透过性的差异。方法 12只雄性Wistar大鼠随机分为正常对照组和糖尿病模型组,每组6只,采用微透析法监测酮康唑凝胶经腹部皮肤给药后大鼠皮下和颈静脉的药物质量浓度,采用LC-MS/MS法检测微透析样品的药物浓度,分析和比较2组大鼠皮下组织药物质量浓度-时间曲线图,计算药动学参数。结果糖尿病大鼠和正常大鼠腹部皮下Cmax分别为(6 699.06±926.02)、(3 447.94±345.00)ng.mL-1,AUC分别为(28 463.39±2 817.85)、(18 149.60±1 103.63)ng.mL-1.h,2组间的差异均有统计学意义(P<0.05,n=6);糖尿病大鼠和正常大鼠颈静脉Cmax分别为(400.887±51.254)、(361.046±98.92)ng.mL-1,AUC分别为(1 622.16±76.23)、(1 469.51±216.46)ng.mL-1.h,2组间的差异无统计学意义(P>0.05,n=6)。结论糖尿病引起的皮肤病理改变会造成酮康唑经皮透过增加,糖尿病患者在使用时需酌情减量,减少毒副作用。

Objective To study the difference of skin permeability of ketoconazole（KTZ） gelatin between normal rats and diabetic rats.Methods 12 male Wistar rats were randomly divided into two groups：normal rats and diabetic model（DM） groups.Microdialysis was used to monitor subcutaneous and jugular venous blood concentration of KTZ by abdominal skin administration.KTZ concerntration in dialysate was quantitatively determined by LC-MS/MS.Subcutaneous/plasma concentration-time curves of two groups were analyzed and compared,and the pharmacokinetic parameters were calculated.Results Subcutaneous drug concentration in diabetic rats was significantly higher than normal rats,and Cmax and AUC compared with the normal group was with significant difference（P0.05）.The subcutaneous Cmax of DM group and control group were（6 699.06±926.02） and（3 447.94±345.00） ng·mL-1,respectively.The subcutaneous AUC of DM group and control group were（28 463.39±2 817.85） and（18 149.60±1 103.63） ng·mL-1·h,respectively.There was significant difference between the two groups（P0.05,n=6）.The jugular vein Cmax of DM group and control group were（400.887±51.254） and（361.046±98.92） ng·mL-1,respectively.The jugular vein AUC of DM group and control group were（1 622.16±76.23） and（1 469.51±216.46） ng·mL-1·h,respectively.There was no significant difference（P0.05,n=6） between the two groups.Conclusion Diabetes induced some pathological changes on skin,which resulted in the increasing of the permeation of KTZ.Therefore,it is necessary to adjust the dose while KTZ or some other topical preparations will be applied on the skin in case of diabetes mellitus,in order to reduce drug side effects and improve the diabetics′ quality of life.