戈舍瑞林缓释植入剂在大鼠体内的药代动力学及药效动力学

Pharmacokinetics and pharmacodynamics of sustained-release implant of goserelin in rats

目的研究不同剂量戈舍瑞林缓释植入剂在大鼠体内的药代动力学及药效动力学特征,以揭示其体内释放过程、时间、剂量和药效之间的关系。方法雄性SD大鼠每只分别sc给予戈舍瑞林缓释植入剂0.3,0.6和1.2 mg。采用HPLC-MS/MS方法测定体内戈舍瑞林浓度及睾酮浓度。WinNonlin 6.3软件计算药代动力学参数。结果所得参数血药浓度-时间曲线下面积（AUC0-t）分别为770±96,1534±299和（3233±777）μg·L^-1·h;药峰浓度（cmax）分别为3.7±0.3,6.8±2.2和（17.6±5.4）μg·L^-1,均与剂量呈明显线性相关,相关系数r分别为0.942和0.923;药峰时间（Tmax）,半衰期（t1/2）,平均滞留时间（MRT）,清除率（Cl）与表观分布容积（Vd）则均无显著差异。给药初期睾酮浓度显著上升,随后快速下降至低浓度水平,随着剂量的增加,睾酮变化并未呈现良好的量效关系,大鼠给予戈舍瑞林缓释植入剂剂量达到每只0.6 mg以上,4 d后均能抑制血浆睾酮水平至理论去势水平（0.5μg·L^-1）,且可以维持至第28天。在给药28～35 d以后恢复至正常水平。结论戈舍瑞林缓释植入剂每只0.3～1.2 mg剂量范围内呈线性药代动力学特性。

OBJECTIVE To illustrate the pharmacokinetics and pharmacodynamics of different dosages of sustained-release implant of goserelin in rats. METHODS The rats received a single dose of sustaineed-release implant of goserelin 0. 3,0. 6 and 1. 2 mg per rat by subcutaneous injection,respectively. Concentrations of goserelin and testosterone in plasma were determined by HPLC-MS /MS. The pharmacokinetic parameters were calculated by WinNonlin6. 3. RESULTS The main pharmacokinetic parameters of the 0. 3,0. 6 and 1. 2 mg per rat were as fowllows： the area under the concentration-time curve（ AUC0- t） was 770 ±96,1534 ±299 and（ 3233 ±777） μg·L^-1·h,and the maximum plasma concentration（ cmax） was 3.7 ±0. 3,6. 8 ±2. 2 and（ 17. 6 ±5. 4） μg·L^-1,respectively. Regression analysis was applied to analyze the relationship between AUC0- tand cmaxat different doses and those relative coefficients were 0. 942 and 0. 923 respectively. AUC0- tand cmaxincreased with the dose in the range of 0. 3- 1. 2 mg per rat. As for other main pharmacokinetic parameters（ peak time,half life,mean residence time,clearance and apparent volume of distribution）,there was no significant difference between the three groups. Testosterone plasma concentration reached the highest level following administration and then kept decreasing to low concentrations. Between 28 d and 35 d,testosterone plasma concentration slowly increased to the normal level. CONCLUSION Pharmacokinetic characteristics of sustainedrelease implant of goserelin in rats show a linear relationship,within the dose range of 0. 3- 1. 2 mg per rat. The results from pharmacodynamic data show that testosterone does not change in a dose-dependent manner at a dose ranging from 0. 3 to 1. 2 mg per rat. Testosterone plasma concentration decreases to theoretical castrate level（ 0. 5 μg·L^-1） after 4 d following a dose of 0.6-1.2 mg per rat.