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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 investigate the pharmacokinetics of levonorgestrel (LNG) and ethynylestradiol (EE) in rabbits and to evaluate the drug accumulation after multiple administrations. Methods: Rabbits were collected blood from the ear vein at different time points after administration of single and multiple doses, and radioimmunoassay (RIA) method was used to determine the blood levels of estrogen / progesterone in rabbits at each time point Concentration, pharmacokinetic software was used to calculate the pharmacokinetic parameters and statistical analysis. Results: The peak LNG concentrations (Cmax) were 1.04 ± 0.12 ng / ml and 2.42 ± 0.60 ng / ml in the low (10 cm2), medium (20 cm2) and high dose (40 cm2) ml and 4.90 ± 1.39 ng / ml respectively (P <0.05). The area under the plasma concentration-time curve (AUC) was 49.93 ± 9.79 h.ng / ml, 115.14 ± 34.25 h.ng/ml and 251.22 ± 80.55 h.ng/ml, respectively (P <0.01) (P <0.05). The mean peak concentrations of serum EE were 112.00 ± 45.50 pg / ml, 139.23 ± 28.23 pg / ml and 290.26 ± 66.62 pg / ml, respectively. There was no significant difference between low dose group (P> 0.05). EE area of plasma concentration-time curve (AUC) were 4.70 ± 1.34 h.ng/ml, 6.59 ± 1.23 h.ng/ml and 16.59 ± 2.33 h.ng/ml, the middle and high dose groups were significant Difference (P <0.01). Evans reference contraceptive patch group serum LNG concentration Cmax of 3.16 ± 1.00 ng / ml, AUC of 155.29 ± 46.14 h.ng/ml, and LNG / EE contraceptive patch medium dose (clinical trial dose to be adopted) phase No significant difference between the two (P> 0.05). Serum EE concentration in the middle dose group was significantly lower than that in the Evra contraceptive patch (P <0.05). After repeated administrations, LNG / EE contraceptive patch 10 cm2 group and 20 cm2 group showed no accumulation of LNG and EE blood concentration in the repeated administration of 10 times, while the Evra patch group repeated administration for 4 times In the accumulation of LNG and EE blood concentration does not appear. Conclusion: The medium dosage of LNG / EE contraceptives has good contraceptive effect and its side effects may be less than that of Evra.