CAJ | 학술논문

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。
목적：연구불동제량과사서림완석식입제재대서체내적약대동역학급약효동역학특정，이게시기체내석방과정、시간、제량화약효지간적관계。방법웅성SD 대서매지분별sc급여과사서림완석식입제0．3，0．6화1．2 mg。채용HPLC-MS/MS방법측정체내과사서림농도급고동농도。WinNonlin 6．3연건계산약대동역학삼수。결과소득삼수혈약농도-시간곡선하면적（AUC0-t ）분별위770±96，1534±299화（3233±777）μg·L-1·h；약봉농도（cmax ）분별위3．7±0．3，6．8±2．2화（17．6±5．4）μg·L-1，균여제량정명현선성상관，상관계수r분별위0．942화0．923；약봉시간（Tmax ），반쇠기（t1/2），평균체류시간（MRT），청제솔（Cl）여표관분포용적（Vd ）칙균무현저차이。급약초기고동농도현저상승，수후쾌속하강지저농도수평，수착제량적증가，고동변화병미정현량호적량효관계，대서급여과사서림완석식입제제량체도매지0．6 mg이상，4 d후균능억제혈장고동수평지이론거세수평（0．5μg·L-1），차가이유지지제28천。재급약28～35 d이후회복지정상수평。결론과사서림완석식입제매지0．3～1．2 mg제량범위내정선성약대동역학특성。
OBJECTIVE Toillustratethepharmacokineticsandpharmacodynamicsofdifferentdos-agesofsustained-releaseimplantofgoserelininrats.METHODS Theratsreceivedasingledoseof sustaineed-release i mplant of goserelin 0.3,0.6 and 1 .2 mg per rat by subcutaneous injection,respec-tively.Concentrations of goserelin and testosterone in plas ma were determined by HPLC-MS/MS.The pharmacokineticparameterswerecalculatedbyWinNonlin6.3.RESULTS Themainpharmacokinetic 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 con-centration(cmax)was 3.7 ±0.3,6.8 ±2.2 and (1 7.6 ±5.4)μg·L-1 ,respectively.Regression analysis was applied to analyze the relationship between AUC0-t and cmax at different doses and those relative coefficients were 0.942 and 0.923 respectively.AUC0-t and cmax increased 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 resi-dence 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 plas ma concentra-tionslowlyincreasedtothenormallevel.CONCLUSION Pharmacokineticcharacteristicsofsustained-release 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-depend-ent 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.