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氨氯地平及左氨氯地平对大鼠体内仑伐替尼药物动力学的影响及其机制

Effect of amlodipine and levamlodipine on the pharmacokinetics of lenvatinib in rats and related mechanisms
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摘要 目的研究氨氯地平及左氨氯地平对仑伐替尼药物动力学的影响并探究相关机制。方法选取18只雄性SD大鼠随机分为3组,包括仑伐替尼(1.2 mg/kg)组、氨氯地平(1.0 mg/kg)联合仑伐替尼组和左氨氯地平(0.5 mg/kg)联合仑伐替尼组,每组各6只。分别用0.5%羧甲基纤维素钠、氨氯地平及左氨氯地平灌胃液预处理8 d,末次灌胃后给予仑伐替尼,并按照规定的采血时间点眼内眦静脉丛采血。采用超高效液相色谱串联质谱(UPLC-MS/MS)法测定大鼠血浆中仑伐替尼的药物浓度,非房室模型计算药物动力学参数。采用RT-q PCR检测大鼠肝组织中细胞色素P4503A1(CYP3A1)、P-糖蛋白(P-gp)和乳腺癌耐药蛋白(BCRP)m RNA表达。符合正态分布的计量资料多组间比较采用单因素方差分析,进一步两两比较采用Dunnett-t检验;不符合正态分布的计量资料多组间比较采用Kruskal-Wallis H检验。结果3组间药时曲线下面积AUC0-∞(F=4.567,P<0.05)、清除率CLz/F(F=5.038,P<0.05)和峰浓度C_(max)(F=11.667,P<0.01)比较差异均存在统计学意义(P值均<0.05),与仑伐替尼组比较,氨氯地平联合仑伐替尼组AUC0-∞升高36.1%(P<0.05)、CLz/F下降26.1%(P<0.05)、C_(max)升高56.7%(P<0.01),左氨氯地平联合仑伐替尼组C_(max)升高37.7%(P<0.05);RT-q PCR结果显示,3组间CYP3A1、P-gp和BCRP m RNA的表达差异均有统计学意义(F值分别为10.160、5.350、5.237,P值均<0.05),与仑伐替尼组比较,氨氯地平联合仑伐替尼组大鼠肝脏CYP3A1、P-gp和BCRP m RNA表达水平明显下降(P值均<0.05),而左氨氯地平联合仑伐替尼组大鼠肝脏中CYP3A1 m RNA表达水平也明显下降(P<0.05)。结论氨氯地平可以增加仑伐替尼的体内暴露量,作用机制可能与抑制肝脏中CYP3A1、P-gp和BCRP的m RNA表达有关;而左氨氯地平仅增加仑伐替尼的峰浓度。 Objective To investigate the effect of amlodipine and levamlodipine on the pharmacokinetics of lenvatinib and related mechanisms.Methods A total of 18 male Sprague-Dawley rats were randomly divided into lenvatinib(1.2 mg/kg)group,amlodipine(1.0 mg/kg)+lenvatinib group,and levamlodipine(0.5 mg/kg)+lenvatinib group,with 6 rats in each group.The rats were pretreated with 0.5%sodium carboxymethyl cellulose,amlodipine or levamlodipine by gavage for 8 days,and lenvatinib was given after the last intragastric administration.Blood samples were collected from the intraocular canthus venous plexus at the specified time points.Ultra-performance liquid chromatography-tandem mass spectrometry was used to measure the plasma concentration of lenvatinib in rats,and a non-compartment model was used to calculate pharmacokinetic parameters.RT-qPCR was used to measure the mRNA expression levels of cytochrome P4503A1(CYP3A1),P-glycoprotein(P-gp),and breast cancer resistance protein(BCRP)in rat liver tissue.A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups,and the Dunnett-t test was used for further comparison between two groups;the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between groups.Results There were significant differences between the three groups in the area under the concentration-time curve AUC0-∞(F=4.567,P<0.05),clearance rate CLz/F(F=5.038,P<0.05),and peak concentration C_(max)(F=11.667,P<0.01).Compared with the lenvatinib group,the amlodipine+lenvatinib group had an increase in AUC0-∞by 36.1%(P<0.05),a reduction in CLz/F by 26.1%(P<0.05),and an increase in C_(max)by 56.7%(P<0.01),and the levamlodipine+lenvatinib group had an increase in C_(max)by 37.7%(P<0.05).RT-qPCR showed that there were significant differences in the mRNA expression levels of CYP3A1,P-gp,and BCRP between the three groups(F=10.160,5.350,and 5.237,all P<0.05),and compared with the lenvatinib group,the amlodipine+lenvatinib group had significant reductions in the mRNA expression levels of CYP3A1,P-gp,and BCRP in rat liver tissue(all P<0.05),while the levamlodipine+lenvatinib group had a significant reduction in the mRNA expression level of CYP3A1 in rat liver tissue(P<0.05).Conclusion Amlodipine can increase the in vivo exposure of lenvatinib possibly by inhibiting the mRNA expression of CYP3A1,P-gp,and BCRP in the liver,while levamlodipine only increases the peak concentration of lenvatinib.
作者 闫彬 曹格溪 邓艳茹 李颖 董占军 白万军 YAN Bin;CAO Gexi;DENG Yanru;LI Ying;DONG Zhanjun;BAI Wanjun(Hebei Medical University,Shijiazhuang 050000,China;Department of Pharmacy,Hebei General Hospital,Shijiazhuang 050000,China;Hebei Key Laboratory of Clinical Pharmacy,Shijiazhuang 050000,China)
出处 《临床肝胆病杂志》 CAS 北大核心 2024年第11期2246-2252,共7页 Journal of Clinical Hepatology
基金 河北省自然科学基金(H2022307063) 政府资助临床医学优秀人才培养项目(202218) 河北省医学适用技术跟踪项目(GZ2022007)。
关键词 肝细胞 大鼠 SPRAGUE-DAWLEY 氨氯地平 仑伐替尼 Carcinoma,Hepatocellular Rats,Sprague-Dawley Amlodipin Lenvatinib
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