目的 对比研究去甲斑蝥素脂质微球注射液(NCTD-LM)和去甲斑蝥酸钠注射液(NCTD-I)连续90 d静脉滴注给予Beagle犬的毒动学特征,并研究毒性剂量下2种制剂在Beagle犬体内的蓄积情况。方法 应用超高效液相色谱-质谱联用(UPLC-MS/MS)法测定各组Beagle犬在首次给药、连续给药44和90 d的血药浓度,并计算毒动学参数。结果 分别静脉滴注给予Beagle犬0.8、1.6和3.2 mg/kg NCTD-LM后,首次给药后AUC_0-t分别为(2.22±0.53)、(4.77±1.13)和(13.4±3.6)h·mg/L,t_1/2分别为(1.37±0.18)、(1.64±0.42)和(1.98±0.25)h;90 d后其AUC_0-t分别为(3.58±0.95)、(11.4±2.0)和(23.5±3.9)h·mg/L,t_1/2分别为(3.87±1.90)、(5.75±3.29)和(5.84±2.45)h;2.4 mg/kg静脉滴注给予Beagle犬NCTD-I后,首次给药和90 d后其血浆AUC_0-t分别为(9.07±2.09)和(14.1±3.0)h·mg/L,t_1/2分别为(2.84±1.34)和(3.53±1.26)h。但各组动物在停药15和30 d后,血药浓度均低于定量下限。结论 NCTD-LM在Beagle犬体内0.8～3.2 mg/kg剂量内呈现非线性药动学特征。2种制剂连续静脉给予Beagle犬90 d,血药浓度、AUC_0-t和t_1/2均随给药时间延长而显著增加,但无长期蓄积作用。

Objective To evaluate the toxicokinetics and in vivo accumulation of norcantharidin lipid microsphere for injection (NCTD-LM) in Beagle's dogs following 90 d repeated iv administration by comparing with sodium demethylcantharidate injection (NCTD-I). Methods An ultra high performance liquid chromatography-tandem mass spectrum method was employed to determine the NCTD in plasma of Beagle's dog after 1, 44, and 90 d repeated iv administration. The toxicokinetic parameters were calculated from the plasma concentration. Results After the first iv administration of 0.8, 1.6, and 3.2 mg/kg NCTD-LM to Beagle's dog, the AUC_0-t were (2.22 ±0.53), (4.77 ±1.13), and (13.43 ±3.64) h·mg/L, respectively, while the t_1/2 were (1.37 ±0.18), (1.64 ±0.42), and (1.98 ±0.25) h, respectively. After the 90 d repeated iv administration of 0.8, 1.6 and 3.2 mg/kg NCTD-LM to Beagle's dog, the AUC_0-t were (3.58 ±0.95), (11.4 ±2.0), and (23.5 ±3.9) h·mg/L, respectively, while the t_1/2 were (3.87 ±1.90), (5.75 ±3.29), and (5.84 ±2.45) h, respectively. For NCTD-I, the AUC_0-t were (9.07 ±2.09) and (14.1 ±3.0) h·mg/L respectively after 1 and 90 d repeated iv administration, while the t_1/2 were (2.84 ±1.34) and (3.53 ±1.26) h. 15 and 30 d after the end of administration, the concentration of NCTD in plasma of Beagle's dog in each group were all dropped below the lowest limit of quantification (LLOQ). Conclusion NCTD displays a nonlinear elimination at the dose range of 0.8—3.2 mg/kg after iv administration of NCTD-LM to Beagle's dog. Over the 90 d repeated iv administration period, the plasma concentration levels, AUC_0-t, and t_1/2 for both NCTD-LM and NCTD-I are increased with time increasing. However, no accumulation of NCTD is observed for the both formulations.

国家科技重大专项重大新药创制:辽宁省国家重大新药创制综合平台(2013ZX09301305)