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Volume 40 Issue 11
Nov.  2024
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Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(11): 2246-2252

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

DOI: 10.12449/JCH241118
  • 1.

    Hebei Medical University，Shijiazhuang 050000，China

  • 2.

    Department of Pharmacy，Hebei General Hospital，Shijiazhuang 050000，China

  • 3.

    Hebei Key Laboratory of Clinical Pharmacy，Shijiazhuang 050000，China

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
  • Corresponding author: BAI Wanjun， baiwanjun0311@163.com （ORCID： 0009-0008-3266-8765）
  • Received Date: 2024-04-01
  • Accepted Date: 2024-05-06
  • Published Date: 2024-11-25
    Abstract
  •   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 P450 3A1 （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 Cmax （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 Cmax by 56.7% （P<0.01）， and the levamlodipine+lenvatinib group had an increase in Cmax 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 invivo 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.

     

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