大鼠重复ig给予N-［（3-烯丙基-2-羟基）苯亚甲基-2-（4-苄基-高哌嗪-1-基）乙酰肼富马酸盐的药动学研究

目的 采用高效液相色谱-串联质谱法（HPLC-MS/MS）测定SD大鼠血浆中N-［（3-烯丙基-2-羟基）苯亚甲基］-2-（4-苄基-高哌嗪-1-基）乙酰肼富马酸盐（SM-1），并计算大鼠重复ig给药的药动学参数，评价SM-1的药动学特征。方法 将60只健康SPF级SD大鼠随机分为阴性对照组、溶媒对照组和SM-1低、中、高剂量组，每组16只动物（阴性对照组和溶媒对照组为6只动物），雌雄各半。每天ig给药1次，各组分别给予水、溶媒或SM-1 50、100、200 mg·kg^-1，给药体积10 mL·kg^-1，连续给药4周，于首次给药和末次给药阶段进行药动学采血测定。采用经验证的HPLC-MS/MS法测定SD大鼠血浆中SM-1浓度。使用Phoenix WinNonlin 7.0软件进行血药浓度-时间数据分析与药动学参数计算。结果 SD大鼠ig给予SM-1后，在50～200 mg·kg^-1剂量，SD大鼠体内的平均峰浓度（C_max）及药时曲线下面积（AUC_0～t）随剂量的增加而增加，各剂量组动物平均C_max及AUC_0～t比值与剂量比相近。连续给药后，低、中、高剂量组均未出现明显的蓄积。雌性大鼠SM-1的暴露高于雄性大鼠。结论 连续给药28 d后，SM-1在大鼠体内未出现明显的蓄积，雌性大鼠SM-1的暴露高于雄性大鼠。

Pharmacokinetics of repeated administration of N-[(3-allyl-2-hydroxy) phenylmethylene]-2-(4-benzyl-piperazine-1-yl) acetylhydrazine fumarate in SD rats

Objective A simple and sensitive high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was used in the determination of N-(3-allyl-2-hydroxy) phenylmethylene] -2- (4-benzyl-piperazine-1-yl) acetylhydrazine fumarate (SM-1) in SD rat plasma. The pharmacokinetics parameters were calculated to evaluate the pharmacokinetic characteristics of repeated administration of SM-1. Methods 60 healthy SPF SD rats were randomly divided into negative control group, solvent control group, SM-1 low, medium and high dose groups with 16 rats in each group (six rats in negative control group and vehicle control group), half male and half female. Each group was given water, solvent or SM-1 50, 100, 200 mg·kg^-1 by gavage administration in volume of 10 mL·kg^-1, once a day for four weeks. Blood samples were collected at the first and last administration stages. HPLC-MS/MS method was used in determination of SM-1 in SD rat plasma. Phoenix WinNonlin 7.0 software was used to analyze the pharmacokinetic characteristic. Results The average C_max and AUC_0-t of SM-1 in SD rats increased with the increase of dose in the range of 50-200 mg·kg^-1, and the average C_max and AUC_0-t ratio of each dose were similar to the dose ratio. After continuous administration, there was no obvious accumulation in low, medium or high dose groups. The exposure of SM-1 in female rats was higher than that in male rats. Conclusion After continuous administration for 28 d, there was no obvious accumulation in low, medium or high dose groups. The exposure of SM-1 in female rats was higher than that in male rats.