新型左炔诺孕酮/炔雌醇复方避孕贴剂的家兔药代动力学研究

Pharmacokinetic Study of Novel Levonorgestrel and Ethinylestradiol Contraceptive Patch on Rabbits

目的:探讨新型左炔诺孕酮(levonorgestrel,LNG)和炔雌醇(ethynylestradiol,EE)在家兔体内的药物动力学特征,评价多次给药后是否出现药物蓄积情况。方法:家兔在单次和多次给药及停止给药后不同时间点耳缘静脉采血,选择放射免疫分析(radioimmunoassay,RIA)法测定各时间点各组家兔雌/孕激素的血药浓度,使用药物动力学软件计算各药物动力学参数并对其进行统计分析。结果:单次给药后受试贴剂低(10cm2)、中(20 cm2)和高剂量(40 cm2)组血清LNG峰浓度(Cmax)分别为1.04±0.12 ng/ml、2.42±0.60 ng/ml和4.90±1.39 ng/ml,3组间有显著差异(P<0.05)。血药浓度-时间曲线下面积(AUC)分别为49.93±9.79h.ng/ml、115.14±34.25 h.ng/ml和251.22±80.55 h.ng/ml,3组间有显著差异(P<0.01);血清EE峰浓度(Cmax)分别为112.00±45.50 pg/ml、139.23±28.23 pg/ml和290.26±66.62 pg/ml,中、高剂量组间有显著差异(P<0.05),而中、低剂量组间无统计学差异(P>0.05)。EE血药浓度-时间曲线下面积(AUC)分别为4.70±1.34 h.ng/ml、6.59±1.23h.ng/ml和16.59±2.33 h.ng/ml,中、高剂量组之间有显著差异(P<0.01)。Evra参比避孕贴剂组血清LNG浓度的Cmax为3.16±1.00 ng/ml,AUC为155.29±46.14 h.ng/ml,与LNG/EE避孕贴剂中剂量组(拟采用的临床试验剂量)相比,两者无显著差异(P>0.05)。中剂量组血清EE浓度与Evra避孕贴剂的相比显著降低(P<0.05)。多次给药后LNG/EE避孕贴剂10 cm2组和20 cm2组在重复给药10次的过程中未出现LNG和EE血药浓度蓄积现象,Evra贴剂组在重复给药4次的过程中未出现LNG和EE血药浓度蓄积现象。结论:中剂量的LNG/EE避孕贴剂具有良好的避孕效果,同时其副作用可能小于Evra。

Objective： To study characteristics of the pharmacokinetics of levonorgestrel （LNG） and ethinylestradiol（EE） contraceptive patch on rabbits and evaluate their accumulation after multiple dosing. Methods： The rabbits were given single and multiple LNG/EE patch and Evra patch in a randomized study. The blood samples were collected at different time points before and after taking the medicine. The serum LNG/EE concentrations were determined by radioimmunoassay method. The pharmacokinetic parameters and relative bioavailability were calculated using DAS software. Results： For single dose, the rabbit serum LNG C in low-dose group, medium-dose group and high-dose group were respectively 1.04 _ 0.12 ng/ml, 2.42±0.60 ng/ml and 4.90 ±1.39 ng/ml. The AUC of LNG were 49.93 ±9.79hong/ml, 115.14± 34.25 hong/ml and 251.22 ± 80.55 hng/ml, respectively showing a significant difference among each other （P〈0.01）. The rabbit serum EE C of low-dose group, middle-dose group and high-dose group were 112.00± 45.50 pg/ml, 139.23 ± 28.23 pg/ml and 290.26 ± 66.62 pg/ml, respectively, having a significant difference between middle-dose group and high-dose group （P〈0.05）. The AUC of EE were 4.70 ±1.34 h-ng/ml, 6,59 ± 1.23 hng/ml and 16.59±2.33 h ong/ml, respectively showing a significant difference between middle-dose group and high-dose group （P〈0.05）. The rabbit serum LNG C in Evra group was 3.16 ± 1.00 ng/ml, the AUC was 155.29 ±46.14 h ng/ml, showing no significant difference compared with LNG/EE middle-dose group. However, the rabbit serum EE of middle-dose group was significantly decreased compared with Evra group. For multiple dose, there was no LNG and EE accumulations in the rabbit serum. Conclusion： LNG/EE contraceptive patch has a steady state within 96 h after dosing which is similar to Evra patch with a good contraceptive effect. There is no accumulation for multiple dosing which may have lower side effects than Evra patch.