目的 测定连续给予注射用酒石酸长春瑞滨胶束的毒动学参数，并与注射用酒石酸长春瑞滨进行比较。方法 选取16只比格犬随机分为4组，雌雄各半，分别连续iv给予注射用酒石酸长春瑞滨胶束低、中、高剂量（0.29、0.58、1.174 mg/kg）与注射用酒石酸长春瑞滨1.174 mg/kg，建立测定比格犬血浆中酒石酸长春瑞滨浓度的液相色谱-串联质谱（LC-MS/MS）法，测定血药浓度，采用DAS3.1.4药动学软件计算动力学参数。结果 比格犬iv给予注射用酒石酸长春瑞滨胶束低、中、高3个剂量，血药浓度、AUC_（0-t）、C_max随给药剂量的增加而增大；连续iv给药，低、中、高剂量组动物血药浓度、AUC_（0-t）、C_max在给药第1、29、71天时均变化不大，无明显蓄积倾向。而注射用长春瑞滨胶连续iv给药后随给药时间延长，动物血药浓度、AUC_（0-t）、C_max有上升趋势，AUC_（0-t）蓄积因子分别为2.08、1.80，C_max蓄积因子分别为2.58、2.32，均有蓄积倾向。结论 注射用酒石酸长春瑞滨胶束与普通注射用酒石酸长春瑞滨毒动学参数比较，无明显的蓄积倾向，可降低长期服药的毒性风险。

Objective To establish a quick method to analyze vinorelbine tartrate in plasma of beagle dogs and compare the toxicokinetics of vinorelbine tartrate micelle for injection and vinorelbine tartrate for injection. Methods Sixteen beagle dogs were selected and divided into four groups, who received multiple dose of 0.29, 0.58 and 1.174 mg/kg vinorelbine tartrate micelle for injection and 1.174 mg/kg vinorelbine tartrate for injection respectively. The plasma concentrations of vinorelbine tartrate micelle were determined by LC-MS/MS. Using DAS3.1.4 pharmacokinetic software to calculate the kinetic parameters. Results The blood concentration, AUC_(0-t) and C_max of beagle dogs increased with the increase of iv dose. The blood concentration, AUC_(0-t) and C_max of beagle dogs in the low, middle and high dose groups did not change significantly at the 1st, 29th and 71st day of administration. After iv continuous administration of vinorelbine for injection, the concentration of blood drug, AUC_(0-t), C_max increased with the increase of administration time. The accumulation factors of AUC_(0-t) were 2.08, 1.80, and C_max were 2.58 and 2.32, respectively. Conclusion Compared with the pharmacokinetic parameters of vinorelbine tartrate for injection, vinorelbine tartrate for injection has no obvious accumulation tendency, which can reduce the risk of long-term toxicity.

R969.1

科技部"重大新药创制"科技重大专项（2015ZX09501004-002-003）