奥美拉唑对多西他赛在乳腺癌大鼠体内药动学的影响

Effects of omeprazole on pharmacokinetics of docetaxel in breast cancer rats

目的研究奥美拉唑对多西他赛在乳腺癌大鼠体内药动学的影响。方法采用7,12-二甲基苯并蒽建立大鼠乳腺癌模型。取18只乳腺癌大鼠随机分成单剂量组、多剂量组和对照组,每组6只。单剂量组灌胃给予奥美拉唑3.5 mg·kg^(-1),每日1次;多剂量组灌胃给予奥美拉唑3.5 mg·kg^(-1),每日2次;对照组每日灌胃给予相同体积生理盐水。持续给药7 d后,分别静脉注射多西他赛10 mg·kg^(-1)。并于给药前(0 min)和给药后1、5、10、20、30、60、120、240、480、600 min收集大鼠血浆。建立高效液相色谱-串联质谱(HPLC-MS/MS)法并测定大鼠血浆中多西他赛浓度,计算药动学参数。同时,考察奥美拉唑对多西他赛在肝微粒体中代谢的影响。结果对照组、奥美拉唑单剂量和多剂量组给药后,乳腺癌大鼠体内多西他赛的主要药动学参数c_(max)、AUC_(0-t)和t_(1/2)分别为(669.35±102.67)、(722.58±72.81)和(701.23±123.45)ng·mL^(-1);(2 010.63±307.23)、(2 487.61±252.43)和(2 875.86±317.55)ng·h·mL^(-1);1.74、2.28和3.01 h;与对照组相比,奥美拉唑单剂量组大鼠体内多西他赛的t_(1/2)显著升高(P<0.05),多剂量组AUC_(0-t)和t_(1/2)显著升高(P<0.05),但c_(max)无显著差异(P>0.05),而奥美拉唑单剂量和多剂量组间的药动学参数无显著差异(P>0.05)。在大鼠肝微粒体中,奥美拉唑可以非竞争性方式抑制多西他赛的代谢。结论奥美拉唑可提高多西他赛在乳腺癌大鼠体内的生物利用度,并减缓消除速率,可能会导致多西他赛药效及毒副作用的增加。

AIM To investigate the effects of omeprazole on pharmacokinetics of docetaxel in breast cancer rats.METHODS The rat breast cancer model was established by 7,12-dimethylbenzanthracene(DMBA),and 18 breast cancer rats were randomly divided into three groups.The rats were gavaged with omeprazole 3.5 mg·kg-1once a day(single dose group),omeprazole 3.5 mg·kg-1twice a day(multiple dose group),and normal saline(control group)for 7 days,respectively,and then intravenous injected with docetaxel 10 mg·kg-1.The blood samples were collected at 0,1,5,10,20,30,60,120,240,480 and 600 min post dose.The determination method of docetaxel in rat plasma by high performance liquid chromatography-mass spectrometry(HPLC-MS/MS)was established,and then the pharmacokinetic parameters were calculated.In the meantime,the effects of omeprazole on metabolism of docetaxel in rat liver microsomes were investigated.RESULTS The mean cmax,AUC0-tand t1/2of docetaxel were(669.35±102.67),(722.58±72.81)and(701.23±123.45)ng·mL-1;(2 010.63±307.23),(2 487.61±252.43)and(2 875.86±317.55)ng·h·mL-1;1.74,2.28 and 3.01 h for the control group,single dose group and multiple doses group.Compared with the control group,increased t1/2of docetaxel was observed in the single dose group(P<0.05),and significantly increased AUC0-tand t1/2of docetaxel were observed in the multiple dose group(P<0.05),but no significant difference was found in cmax(P>0.05),and no significant pharmacokinetic difference between the single and multiple groups was observed(P<0.05).In rat microsomes,omeprazole inhibited the metabolism of docetaxel in a non-competitive manner.CONCLUSION Co-administering with omeprazole could increase the in vivo exposure of docetaxel and decrease its eliminate rate in breast cancer rats,which might lead to an increase in not only therapeutic but also toxic effects of docetaxel.