在体微透析技术研究低相对分子质量肝素凝胶经皮给药大鼠体内药动学特征

Analysis of Pharmacokinetic Characteristics of Low Molecular Weight Heparin Gel after Transdermal Adminstration by in Vivo Microdialysis Technique Combined with Colorimetric Method

目的考察低相对分子质量肝素凝胶经皮给药后大鼠皮肤和血液中低分子量肝素含量,评价其透皮药动学特征。方法SD大鼠腹部脱毛后经皮给予低分子量肝素凝胶,应用微透析采样技术结合比色法测定大鼠皮肤中低分子量肝素浓度随时间变化的影响,通过剪尾取血和Coatest Heparin试剂盒测定大鼠血液中低分子量肝素浓度随时间变化的影响。结果低分子量肝素凝胶经皮给药后,大鼠皮肤药物浓度达峰时间(tmax)为270 min、皮下最大药物浓度(cmax)是(4.40±0.54)IU·m L-1、t1/2为(137.04±87.98)min、AUC0-t为(911.76±330.69)IU·m L-1·min-1、MRT0-t为(322.67±40.94)min;大鼠血液内药物浓度达峰时间(tmax)为540 min、血液内最大药物浓度(cmax)是(2.23±0.40)IU·m L-1、t1/2为(294.99±183.74)min、AUC0-t为(110.59±212.41)IU·m L-1·min、MRT0-t为(422.48±52.96)min。结论在体微透析技术结合比色法可用于低分子量肝素凝胶透皮吸收药动学特征,方法操作简便、灵敏度高、专属性强。低分子量肝素凝胶经皮给药后具有缓慢透皮、浓度稳定的特点。

OBJECTIVE To determine the concentrations of low molecular weight heparin （LMWH） in dermal and plasma of rats after administration of LMWH gel to evaluate its pharmacokinetic characteristics. METHODS The rats were treated with abdominal hair removal, followed by administrating LMWH gel. The concentrations of LMWH in the dermal of rats at different time points were measured by microdialysis technique combined with colorimetric method, and the concentrations of LMWH in the blood of rats at differ- ent time points were measured by cutting-tail method and Coatest Heparin Kit. RESULTS The LMWH tmax in dermis was 270 min, Cmax was （4. 40 ±0. 54） IU· mL-1, t1/2 was （137.04±87.98） min, AUC0-t, was （911.76 ±330. 69） IU· mL · min-1 , MRTo-t, was （322. 67±40. 94） min; the LMWH t in plasma was 540 min, Cmax was （2. 23±0. 40） IU · mL-1 , t1/2 was （294. 99 ± 183.74） min, AUCo-t, was （110. 59 ±212. 41） IU · mL · min, MRT0-t, was （422. 48 ±52. 96） min after LMWH gel was percutaneous adminis- trated. CONCLUSION In vivo microdialysis technique combined with colorimetric method can be used for the evaluation of pharma- cokinetic characteristics of LMWH gel. The method has the advantages of simple operation with high sensitivity and specificity. LMWH gel have the characteristics of slow transdermal penetration speed and stabilized concentration.