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

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

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-150、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。

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-150,100,200 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.