基于内标微透析技术同步分析尼古丁透皮贴剂在血液与皮肤的药动学

目的：利用内标微透析采样技术，同步研究尼古丁透皮贴剂的血液和皮肤局部药动学特征，获得其较全面的体内药动学规律。方法：以健康SD大鼠为实验动物，将尼古丁透皮贴剂经皮给药，磷酸可待因作为微透析采样的内标物，采集不同时间点血液和皮肤微透析样品，用高效液相色谱法（HPLC）进行测定，利用DAS 2.1药动学软件计算相关药动学参数。结果：尼古丁在血液和皮肤的平均滞留时间（MRT_0-∞）分别为（16 986.00±486.00）min和（1 597.00±851.00）min，药时曲线下面积（AUC_0-∞）分别为（19 235.42±1 801.92）mg·mL^-1·min和（56 328.82±24 900.42）mg·mL^-1·min，达峰浓度（C_max）分别为（2.00±0.50）mg·L^-1和（32.00±5.00）mg·L^-1，达峰时间（t_max）分别为（325±200）min和（570±106）min。尼古丁在血液与皮肤的药动学参数相比，AUC_0-∞、C_max、t_max在皮肤中较大，MRT_0-∞在血液中较大。结论：尼古丁透皮贴剂经皮给药后，在血液与皮肤的药动学规律存在明显的差异与联系，药动学参数证明尼古丁通过透皮渗透在皮肤中以相对较高的浓度蓄积，能达到快速、有效的吸收，进入血液后血药浓度相对较低且维持稳定，发挥显著长效作用。

Pharmacokinetics of nicotine patch in blood and skin based on internal standard microdialysis technique

OBJECTIVE To study the pharmacokinetics of nicotine transdermal system in blood and skin simultaneously by internal standard microdialysis sampling technique, and to obtain its comprehensive metabolism characteristics in vivo. METHODS Healthy SD rats were used as experimental animals and given transdermal nicotine patch. Codeine phosphate was used as internal standard for microdialysis. Blood and skin microdialysis samples were collected at different time points and determined by HPLC. Pharmacokinetic parameters were calculated and analyzed by DAS 2.1 pharmacokinetic software. RESULTS The mean residence time (MRT_0-∞) of nicotine in blood and skin was (16 986.00±486.00) and (1597.00±851.00) min, respectively. The area under the concentration-time curve (AUC_0-∞) was (19 235.42±1 801.92) and (56 328.82±24 900.42) mg·mL^-1·min, respectively. The maximum concentration (C_max) was (2.00±0.50) and (32.00±5.00) mg·L^-1, respectively. The maximum time (t_max) was (325±200) and (570±106) min, respectively. Compared with the pharmacokinetic parameters of nicotine in blood and skin, the AUC_0-∞,C_max and t_max of nicotine in skin was higher than those in blood, while the MRT_0-∞ in blood was longer than that in skin. CONCLUSION After transdermal administration of nicotine patch, significant differences and relations of pharmacokinetics were observed between blood and skin. The pharmacokinetic parameters indicated that nicotine can accumulate in the skin at a relatively high concentration through transdermal penetration, and can be absorbed rapidly and effectively. After entering the blood,the blood drug concentration of nicotine was relatively low and remained stable,exerting a significant long-lasting effect.