艾托格列净对索拉非尼和多纳非尼在大鼠体内药动学的影响及机制研究  

Effect and mechanism of ertugliflozin on pharmacokinetic of sorafenib and donafenib in rats

作　　者：邓艳茹 王智[1,3] 曹格溪 闫彬 李颖 董占军[1,2,3] DENG Yanru;WANG Zhi;CAO Gexi;YAN Bin;LI Ying;DONG Zhanjun(Dept.of Pharmacy,Hebei General Hospital,Shijiazhuang 050051,China;School of Pharmacy,Hebei Medical University,Shijiazhuang 050051,China;Hebei Key Laboratory of Clinical Pharmacy,Shijiazhuang 050051,China)

机构地区：[1]河北省人民医院药学部,石家庄050051 [2]河北医科大学药学院,石家庄050017 [3]河北省临床药学重点实验室,石家庄050051

出　　处：《中国药房》2025年第7期826-831,共6页China Pharmacy

基　　金：河北省自然科学基金项目(No.H2022307063);河北省医学科学研究课题(No.20250297)。

摘　　要：目的研究艾托格列净对索拉非尼和多纳非尼在大鼠体内药动学的影响,并探究相关机制。方法将24只雄性SD大鼠随机分成4组,每组6只。A、B组大鼠连续7 d分别灌胃0.5%羧甲基纤维素钠和艾托格列净(1.5 mg/kg),第7天给药后均灌胃索拉非尼(100 mg/kg);C、D组大鼠前7 d灌胃处理分别与A、B组一致,在第7天给药后均灌胃多纳非尼(40 mg/kg)。各组大鼠于索拉非尼或多纳非尼给药前和给药后不同时间点采集血样,采用超高效液相色谱-串联质谱法分别测定A、B组大鼠血浆中索拉非尼质量浓度和C、D组大鼠血浆中多纳非尼质量浓度,利用DAS 2.1.1软件计算药动学参数。另取6只大鼠随机分为空白对照组和艾托格列净给药组,每组3只。空白对照组大鼠灌胃0.5%羧甲基纤维素钠,艾托格列净给药组大鼠灌胃艾托格列净(1.5 mg/kg),每天1次,连续7 d。末次给药后,检测大鼠肝脏和小肠组织中尿苷二磷酸葡萄糖醛酸转移酶1A7(UGT1A7)、乳腺癌耐药蛋白(BCRP)和P-糖蛋白(P-gp)m RNA表达水平。结果与A组比较,B组大鼠血浆中索拉非尼的药-时曲线下面积(AUC_(0-t))、AUC_(0-∞)、峰浓度(c_(max))、达峰时间(t_(max))、平均滞留时间(MRT_(0-t))、MRT_(0-∞)均显著降低(P<0.05),清除率(CL)和表观分布容积(V)均显著升高(P<0.05);与C组比较,D组大鼠血浆中多纳非尼的AUC_(0-t)、AUC_(0-∞)、c_(max)、t_(max)、MRT_(0-t)均显著降低(P<0.05),V和CL均显著升高(P<0.05)。连续7 d灌胃艾托格列净对大鼠肝脏和小肠组织中UGT1A7、P-gp、BCRP m RNA的表达无显著影响。结论艾托格列净可影响索拉非尼和多纳非尼在大鼠体内的药动学过程,减少两者的体内暴露量,但其作用机制可能并非是通过调控相关代谢酶和转运体;临床联合用药时应警惕药物治疗效果不佳可能导致的疾病进展。OBJECTIVE To investigate the effects of ertugliflozin on pharmacokinetic of sorafenib and donafenib in rats and explore the mechanism.METHODS Twenty-four male SD rats were randomly divided into four groups,with 6 rats in each group.Groups A and B were respectively gavaged with 0.5%sodium carboxymethyl cellulose solution and ertugliflozin(1.5 mg/kg)for 7 consecutive days,and both were given sorafenib(100 mg/kg)on the 7th day.Groups C and D were administered intragastrically in the same way as those in Groups A and B,respectively,for the first 7 days;after the drug administration on the 7th day,all rats in Groups C and D were further gavaged with donafenib(40 mg/kg).Blood samples were collected at different time points before and after administration of sorafenib or donafenib,the concentrations of sorafenib in plasma of rats in groups A and B and donafenib in groups C and D were determined by UPLC-MS/MS method.The pharmacokinetic parameters were calculated by DAS 2.1.1 software.Six additional rats were randomly divided into blank control group and ertugliflozin group,with three rats in each group.Blank control group was given 0.5%sodium carboxymethyl cellulose intragastrically,while rats in ertugliflozin group were given ertugliflozin(1.5 mg/kg)once a day for 7 consecutive days.After the last administration,the mRNA expression levels of uridine diphosphate glucuronosyl transferase 1A7(UGT1A7),breast cancer resistance protein(BCRP),and P-glycoprotein(P-gp)in the liver and small intestine tissues of the rats were detected.RESULTS Compared with group A,the AUC_(0-t),AUC_(0-∞),c_(max),tmax,MRT_(0-t) and MRT_(0-∞)of sorafenib in group B were decreased significantly,while CL and V were increased significantly.Compared with group C,the AUC_(0-t),AUC_(0-∞),tmax,c_(max) and MRT_(0-t) of donafenib in group D were decreased significantly,while V and CL were increased significantly(P<0.05).mRNA expression of UGT1A7,P-gp and BCRP in the liver tissue and small intestine of rats were not significantly affected after intraga

关 键 词：艾托格列净 索拉非尼 多纳非尼 药动学 超高效液相色谱-串联质谱法 

分 类 号：R969.1[医药卫生—药理学]