目的 采用高效液相色譜-串聯(lián)質(zhì)譜法（HPLC-MS/MS）測(cè)定SD大鼠血漿中N-［（3-烯丙基-2-羥基）苯亞甲基］-2-（4-芐基-高哌嗪-1-基）乙酰肼富馬酸鹽（SM-1），并計(jì)算大鼠重復(fù)ig給藥的藥動(dòng)學(xué)參數(shù)，評(píng)價(jià)SM-1的藥動(dòng)學(xué)特征。方法 將60只健康SPF級(jí)SD大鼠隨機(jī)分為陰性對(duì)照組、溶媒對(duì)照組和SM-1低、中、高劑量組，每組16只動(dòng)物（陰性對(duì)照組和溶媒對(duì)照組為6只動(dòng)物），雌雄各半。每天ig給藥1次，各組分別給予水、溶媒或SM-1 50、100、200 mg·kg^-1，給藥體積10 mL·kg^-1，連續(xù)給藥4周，于首次給藥和末次給藥階段進(jìn)行藥動(dòng)學(xué)采血測(cè)定。采用經(jīng)驗(yàn)證的HPLC-MS/MS法測(cè)定SD大鼠血漿中SM-1濃度。使用Phoenix WinNonlin 7.0軟件進(jìn)行血藥濃度-時(shí)間數(shù)據(jù)分析與藥動(dòng)學(xué)參數(shù)計(jì)算。結(jié)果 SD大鼠ig給予SM-1后，在50～200 mg·kg^-1劑量，SD大鼠體內(nèi)的平均峰濃度（C_max）及藥時(shí)曲線下面積（AUC_0～t）隨劑量的增加而增加，各劑量組動(dòng)物平均C_max及AUC_0～t比值與劑量比相近。連續(xù)給藥后，低、中、高劑量組均未出現(xiàn)明顯的蓄積。雌性大鼠SM-1的暴露高于雄性大鼠。結(jié)論 連續(xù)給藥28 d后，SM-1在大鼠體內(nèi)未出現(xiàn)明顯的蓄積，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-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.

R285.51

“十三五”國家“重大新藥創(chuàng)制”科技重大專項(xiàng)（2018ZX09201017-001）