黄体酮阴道环在家兔的药代动力学研究

Study on Pharmacokinetics of the Progesterone-releasing Vaginal Rings in Rabbits

目的:提供研制可供哺乳期妇女避孕的黄体酮阴道环的药理学依据。方法:将18只去卵巢后2周的新西兰雌兔随机分为3组:阴道环低剂量组(175mg,A组)、高剂量组(350mg,B组)及肌注组(C组),分别在放置阴道环及肌注黄体酮前后不同时点取静脉血,用磁性分离酶联免疫法测定兔血清中黄体酮的浓度,用PK-Graph程序计算药代动力学参数。结果:黄体酮阴道环和黄体酮注射剂在兔体内的药代动力学符合二室开放模型。主要药代动力学参数分别是A组:Tmax:2.23±1.3h,Cmax:47.64±23.58ng/ml,T1/2:818.08±511.77h,AUC:16115.11±8398.88ng·ml·h-1;B组:Tmax:2.03±1.33h,Cmax:74.04±24.57ng/ml,T1/2:730.31±306.49h,AUC:28751.95±7151.95ml·h-1;C组:Tmax:1.54±0.77h,Cmax:138.88±60.96ng/ml,T1/2:2.55±0.89h。其中A组的AUC(56d)明显低于B组,二者有显著性差异(P<0.05);A组和B组的Cmax均低于C组,差异显著(P<0.05);A组和B组的T1/2均明显高于C组(P<0.01),但A、B组间无差异。结论:与传统的黄体酮注射剂相比,黄体酮阴道环的药代动力学参数呈现明显的长效缓释特征。应可成为安全长效且使用方便的哺乳期避孕药具。

Objective： To provide the pharmacological evidence for development of the progesterone vaginal ring using for contraception in lactating women. Methods： Eighteen rabbits after ovariectomy were divided into three groups randomly： high-dose （350 mg） vaginal ring group（group A）, low-dose （175 mg） vaginal ring group（group B） and injection group（660 μg）（group C）. Blood samples were taken immediately before and after insertion of progesterone vaginal ring or injecting at different time-point. The serum progesterone concentrations in rabbits were mensured with immunosystems and PK-Graph software was used to calculate pharmacokinetic parameters. Results： Pharmacokinetics of vaginal rings and injectable were found to be in agreement with two-compartment open model. Values of main pharmacokinetic parameters are as follows： group A： T1/2：818.08 ± 511.77 h, AUC： 16 115.11 ± 8 398.88 ng · ml · h^-1 Cmax： 47.64 ± 23.58 ng/ml, Tmax： 2.23 ± 1.3 h; group B： T1/2： 730.31 ± 306.49 h, AUC： 2 871.95 ± 7 151.95 ng · ml · h^-1, Cmax： 74.04 ± 24.57 ng/ml, Tmax： 2.03 ± 1.33 h; group C： T1/2：2.55 ± 0.89 h, Cmax： 138.88 ± 60.96 ng/ml, Tmax： 1.54 ± 0.77 h. The AUC（56 d） of group A was low then group B and the Cmax of group A and group B were all lower than group C. There were obvious differences between them. Conclusion： Compared with traditional progesterone injectable, the pharmacokinetic parameters of progesterone vaginal rings presented significant slowing releasing character. So if the progesterone vaginal ring to be developed for clinic use has the similar pharmacokinetic character, it should be a safe, long-acting and convenient contraceptive used for lactating women.