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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

闫彬 曹格溪 邓艳茹 李颖 董占军 白万军

引用本文:
Citation:

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

DOI: 10.12449/JCH241118
基金项目: 

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)

伦理学声明:本研究方案于2022年4月15日经由河北省人民医院实验动物伦理委员会审批,批号:202216,符合实验室动物管理与使用准则。
利益冲突声明:本文不存在任何利益冲突。
作者贡献声明:闫彬负责查阅文献、实验设计、实验操作及撰写论文;曹格溪、邓艳茹和李颖负责协助实验设计并解决实验中遇到的问题;董占军和白万军负责拟定写作思路,指导撰写文章并最后定稿。
详细信息
    通信作者:

    白万军, baiwanjun0311@163.com (ORCID: 0009-0008-3266-8765)

Effect of amlodipine and levamlodipine on the pharmacokinetics of lenvatinib in rats and related mechanisms

Research funding: 

Hebei Natural Science Foundation Project (H2022307063);

Government-funded Program for Outstanding Clinical Medical Talent Development (202218);

Hebei Provincial Medical Applicable Technology Tracking Project (GZ2022007)

More Information
  • 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-qPCR检测大鼠肝组织中细胞色素P450 3A1(CYP3A1)、P-糖蛋白(P-gp)和乳腺癌耐药蛋白(BCRP)mRNA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/FF=5.038,P<0.05)和峰浓度CmaxF=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)、Cmax升高56.7%(P<0.01),左氨氯地平联合仑伐替尼组Cmax升高37.7%(P<0.05);RT-qPCR结果显示,3组间CYP3A1、P-gp和BCRP mRNA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 mRNA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 mRNA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mRNA表达有关;而左氨氯地平仅增加仑伐替尼的峰浓度。

     

  • 图  1  分析物和内标的二级质谱图

    注: a,仑伐替尼;b,2H5-仑伐替尼。

    Figure  1.  MS/MS spectra of analyte and IS

    图  2  分析物和内标化合物的典型色谱图

    注: Ⅰ,仑伐替尼;Ⅱ,2H5-仑伐替尼(内标)。a,空白血浆;b,定量下限仑伐替尼血浆;c,实际灌胃仑伐替尼后大鼠血浆。

    Figure  2.  Typical MRM chromatograms of analyte and IS

    图  3  单独灌胃仑伐替尼和联合氨氯地平或左氨氯地平后仑伐替尼的血药浓度-时间曲线

    注: a,96 h内血药浓度-时间曲线;b,12 h内血药浓度-时间曲线。

    Figure  3.  Plasma concentration-time curves of LEN after oral LEN alone andcombined with AML or LAML

    图  4  大鼠肝脏CYP3A1、P-gp、BCRP的相对mRNA表达

    Figure  4.  Relative mRNA expression of CYP3A1, P-gp, BCRP in rat liver

    表  1  引物序列

    Table  1.   Primer sequences

    基因 正向引物序列 反向引物序列
    GADPH 5'-GCCTTCCGTGTTCCTACC-3' 5'-GCCTGCTTCACCACCTTC-3'
    P-gp 5'-TCTGGTATGGGACTTCCTTGGT-3' 5'-TCCTTGTATGTTGTCGGGTTTG-3'
    BCRP 5'-TGAAGAGTGGCTTTCTAGTCCG-3' 5'-TTGAAATTGGCAGGTTGAGGTG-3'
    CYP3A1 5'-TGCATTGGCATGAGGTTTGC-3' 5'-TTCAGCAGAACTCCTTGAGGG-3'
    下载: 导出CSV

    表  2  大鼠血浆中仑伐替尼的精密度与准确度

    Table  2.   Precision and accuracy of LEN in rat plasma

    理论质量浓度 批内(n=6) 批间(n=18)
    实测质量浓度(ng/mL) RSD(%) RE(%) 实测质量浓度(ng/mL) RSD(%) RE(%)
    2 ng/mL 2.09±0.12 5.6 4.5 2.05±0.09 4.6 2.7
    5 ng/mL 5.47±0.15 2.7 9.0 5.45±0.14 2.5 9.0
    100 ng/mL 102.90±3.56 3.5 2.9 103.22±4.38 4.2 3.2
    2 000 ng/mL 2 068.33±126.56 6.1 3.4 2 067.78±107.73 5.2 3.4
    下载: 导出CSV

    表  3  大鼠血浆中仑伐替尼的提取回收率和基质效应

    Table  3.   Extraction recovery and matrix effect of LEN in rat plasma

    理论质量浓度 提取回收率(%) RSD(%) 基质效应(%) RSD(%)
    2 ng/mL 88.25±5.49 6.2 100.00±12.6 12.6
    100 ng/mL 97.84±4.48 4.6 98.32±4.54 4.6
    2 000 ng/mL 97.91±3.82 3.9 104.23±4.00 3.7
    下载: 导出CSV

    表  4  在不同条件下大鼠血浆中仑伐替尼的稳定性

    Table  4.   Stability of LEN in rat plasma under various conditions

    条件

    理论质量

    浓度(ng/mL)

    实测质量

    浓度(ng/mL)

    精密度

    RSD(%)

    准确度

    RE(%)

    室温8 h 5 5.47±0.11 2.0 9.4
    100 103.85±6.58 6.3 3.9
    2 000 2 053.33±107.83 5.3 2.7
    进样器中12 h 5 5.40±0.16 2.9 8.1
    100 102.75±3.22 3.1 2.8
    2 000 2 081.67±106.47 5.1 4.1
    -20 ℃冻融3次 5 5.42±0.16 2.9 8.3
    100 105.83±3.76 3.6 5.8
    2 000 1 945.00±106.16 5.5 -2.8
    -20 ℃ 30 d 5 5.31±0.11 2.0 6.2
    100 102.58±6.39 6.2 2.6
    2 000 1 928.33±51.15 2.7 -3.6
    下载: 导出CSV

    表  5  单独使用及联合氨氯地平或左氨氯地平时仑伐替尼的药代动力学参数

    Table  5.   Pharmacokinetic parameters of lenvatinib alone andcombined with AML or LAML

    参数

    仑伐替尼组

    n=6)

    仑伐替尼联合

    氨氯地平组(n=6)

    仑伐替尼联合

    左氨氯地平组(n=6)

    统计值 P
    AUC0-t (μg/L·h) 9 807.06±1 390.15 13 416.18±3 350.05 11 963.61±2 347.96 F=3.393 0.061
    AUC0-∞(μg/L·h) 11 142.51±2 246.41 15 160.55±3 308.921) 12 456.64±2 788.95 F=4.567 0.028
    t1/2(h) 55.22±37.64 74.10±50.40 35.01±13.90 F=2.317 0.133
    Tmax(h) 1.50(0.50~3.00) 1.00(0.50~3.00) 1.00(1.00~2.00) H=2.686 0.261
    Vz/F(L/kg) 8.18±4.81 8.63±6.00 4.96±1.89 F=1.065 0.369
    CLz/F(L·h-1·kg-1 0.11±0.02 0.08±0.021) 0.10±0.02 F=5.038 0.021
    Cmax(μg/L) 1 238.33±164.25 1 940.00±344.272) 1 705.00±197.051) F=11.667 0.001

    注:AUC0-t,0到最后一个采血点的药物浓度曲线下面积;AUC0-∞,时间从0到无穷大的药物浓度曲线下面积;t1/2,药物体内消除半衰期;Tmax,达峰时间;Vz/F,表观分布容积;CLz/F,清除率;Cmax,药峰浓度。与仑伐替尼组比较,1)P<0.05, 2)P<0.01。

    下载: 导出CSV
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