抗抑郁药对他莫昔芬及其代谢物在大鼠体内外代谢的影响

The effects of Antidepressant on the metabolism of tamoxifen and its metabolites in rats in vivo and in vitro

目的研究不同抗抑郁药物在大鼠体内外对他莫昔芬(TAM)和N-去甲基他莫昔芬(NDT)的影响。方法将20只雌性Sprague-Dawley(SD)大鼠随机分成四组:A组对照组、B组帕罗西汀组(6.25 mg/kg)、C组度洛西汀组(12.5 mg/kg)、D组氟伏沙明组(12.5 mg/kg)。30 min后给予10 mg/kg TAM,通过尾静脉采血收集各时间点大鼠血浆样本,建立UPLC-MS/MS法测定样本中TAM和NDT血药浓度。另外,建立以抗抑郁药物为抑制剂,TAM为底物的大鼠肝微粒体体外孵育体系,在体外评估不同抗抑郁药物对TAM体外代谢的影响。结果体内研究结果显示,B组与A组比较,TAM的AUC增加84.0%(P<0.01),Vz/F减少46.6%(P<0.05),另外NDT的AUC和Cmax分别增加45.3%(P<0.01)和89.1%(P<0.05),CLz/F降低37.5%(P<0.05)。C组与A组相比,TAM的Vz/F减少48.3%(P<0.05),其余药动学参数均有明显变化但无显著差异。氟伏沙明对TAM和NDT的药动学参数均无显著性影响。体外研究中,100μmol/L浓度的帕罗西汀、度洛西汀和氟伏沙明在大鼠肝微粒体中对TAM代谢的抑制率分别为62.00%、69.67%、79.00%。结论帕罗西汀和度洛西汀对大鼠体内外TAM及其代谢产物的代谢过程均有不同程度的抑制作用。提示临床使用TAM的乳腺癌患者需谨慎联用帕罗西汀和度洛西汀。

Objective To study the effect of antidepressants on tamoxifen metabolism in rats and in rat liver microsomes.Methods A total of twenty female Sprague-Dawley(SD)rats were randomly and evenly divided into four groups:Group A(the control group),Groups B(Paroxetine;6.25 mg/kg),C(Duloxetine;12.5 mg/kg),and D(Fluvoxamine;12.5 mg/kg).30 min later,a dose of 10 mg/kg tamoxifen was administered by gavage.Plasma was collected from the tail vein and determined.An UPLC-MS/MS method was established to accurately measuring the concentrations of tamoxifen and its metabolites in vivo of rats.Moreover,an in vitro incubation system of rat liver microsomes with antidepressant(as an inhibitor)and tamoxifen(as a substrate)was established to evaluate the effect on the metabolism of tamoxifen in rat liver microsomes.Results Compared with group A,the AUC of tamoxifen in group B was increased by 84.0%(P<0.01),and the Vz/F decreased by 46.6%,with statistical significance(P<0.05).Meanwhile,the AUC and Cmax of N-desmethyl TAM in group B was increased by 45.3%(P<0.01)and 89.1%(P<0.05),respectively,then the CLz/F decreased by 37.5%(P<0.05),the difference was significant.Compared with the group A,the Vz/F of tamoxifen in the group C were decreased by 48.3%,with statistical significance(P<0.05).The other pharmacokinetic parameters in the group C were changed,but there was no significant difference in vivo.There was no significant difference in the parameters between the group D and A.In vitro studies,100μmol/L of paroxetine,duloxetine and fluvoxamine inhibited tamoxifen metabolism in rat liver microsomes by 62.00%,69.67%,79.00%,respectively.Conclusion Paroxetine and duloxetine showed varying degrees of inhibitory effects on tamoxifen.We should strive to avoid paroxetine or duloxetine in tamoxifen-treated patients in clinical practice.