甲氨蝶呤与左乙拉西坦在大鼠体内的相互作用研究  

Study on the interaction between methotrexate and evetiracetam in rats

作　　者：薛朝军 李倩[2] 支旭然[1] 李颖[2] 李宵[1] 董占军[2,1] XUE Chao-jun;LI Qian;Zhi Xu-ran;LI Ying;LI Xiao;DONG Zhan-jun(Graduate School of Hebei Medical University,Shijiazhuang 050017;Department of Pharmacy,Hebei General Hospital,Shijiazhuang 050051)

机构地区：[1]河北省人民医院药学部,河北石家庄050051 [2]河北医科大学研究生学院,河北石家庄050017

出　　处：《中国药理学通报》2018年第7期970-977,共8页Chinese Pharmacological Bulletin

基　　金：河北省医学科学研究重点课题计划项目(No 20130417)

摘　　要：目的研究口服甲氨蝶呤与左乙拉西坦在大鼠体内的相互作用及肝肾毒性,为临床合理使用两药提供一定的理论依据。方法雄性SD大鼠随机分为3组:1 mg·kg^(-1)甲氨蝶呤组、180 mg·kg^(-1)左乙拉西坦组、合用组,每组5只,用于药代动力学参数研究、肾脏排泄研究、肝肾毒性研究。本实验样品均采用超高效液相色谱-串联质谱(UPLC/MS/MS)法测定。结果两药合用后,甲氨蝶呤的C_(max)、AUC_(0-t)、T_(max)值升高,T_(1/2)、Cl、MRT值下降,各参数差异有统计学意义。左乙拉西坦的T_(max)、T_(1/2)、Cl、MRT有一定的上升趋势,AUC_(0-t)有一定的下降趋势,各参数差异无统计学意义;两药合用后,甲氨蝶呤的肾排泄明显增加,左乙拉西坦的肾排泄明显降低;两药合用后大鼠的肝肾毒性明显增加。结论口服合用甲氨蝶呤和左乙拉西坦后,左乙拉西坦明显增加甲氨蝶呤在大鼠体内的吸收,使其血药浓度升高、肾排泄增加,造成明显的肝肾损伤,提示两药合用需进行剂量调整。Aim Study the interaction between methotrexate and levetiracetam after oral administration and hepatorenal toxicity in rats,to provide theoretical basis for the clinical rational use of two drugs. Methods Male SD rats（ 250 ± 20） g were selected as experimental animals. Rats were randomly divided into 3 groups（ 1 mg·kg^（-1） methotrexate group,180 mg·kg^（-1） levetiracetam group,combined group）,5 rats in each group. The following experiment was carried out：（ 1） pharmacokinetic parameters study;（ 2） renal excretion study;（ 3） liver and kidney toxicity study. All samples were determined by ultra performance liquid chromatography-tandem mass spectrometry（ UPLC/MS/MS）. Results After the combination of two drugs,the C_（max）,AUC_（0-t） and Tmax of methotrexate increased,T_（1/2）,Cl and MRT of methotrexate decreased,the differences was statistically significant. The T_（max）,T_（1/2）,Cl,MRT of levetiracetam had a certain upward trend,AUC_（0-t） had a certain downward trend, the differences has no statistically significant. After combination of two drugs,the renal excretion of methotrexate increased significantly,the renal excretion of levetiracetam decreased significantly and hepatorenal toxicity increased significantly. Conclusion After combination of two drugs by oral administration,Levetiracetam significantly increased methotrexate absorption in rats.Levetiracetam increased the plasma concentration and renal excretion of methotrexate and caused hepatorenal toxicity significantly. It is suggested that dose adjustment is necessary for combination of two drugs.

关 键 词：左乙拉西坦 甲氨蝶呤 相互作用 UPLC/MS/MS 药动学 大鼠 

分 类 号：R-33[医药卫生] R332.61