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Volume 41 Issue 9
Sep.  2025
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Article Navigation >  Journal of Clinical Hepatology  > 2025  >  41(9): 1853-1860

Pharmacokinetic interactions between empagliflozin and donafenib/lenvatinib in rats

DOI: 10.12449/JCH250921

  • Department of Pharmacy，Hebei Key Laboratory of Clinical Pharmacy，Hebei General Hospital，Shijiazhuang 050017，China

Research funding:

Natural Science Foundation of Hebei Province (H2022307063);

Medical Science Research Project of Hebei (20250297)

More Information
  • Corresponding author: DONG Zhanjun， 13313213656@126.com （ORCID： 0000-0001-5349-4970）
  • Received Date: 2025-03-11
  • Accepted Date: 2025-05-15
  • Published Date: 2025-09-25
    Abstract
  •   Objective  To investigate the influence of empagliflozin combined with donafenib or lenvatinib on the pharmacokinetic parameters of each drug， and to provide a reference for combined medication in clinical practice.  Methods  A total of 48 healthy male Sprague-Dawley rats were divided into 8 groups： empagliflozin group 1 and 2， donafenib group， lenvatinib group， donafenib pretreatment+empagliflozin group， lenvatinib pretreatment + empagliflozin group， empagliflozin pretreatment+donafenib group， and empagliflozin pretreatment+lenvatinib group， with 6 rats in each group. The doses of empagliflozin， donafenib， and lenvatinib were 2.5 mg/kg， 40 mg/kg， and 1.2 mg/kg， respectively. The rats in the empagliflozin group， donafenib group， and lenvatinib group were given a blank solvent by gavage for 7 consecutive days， followed by a single dose of empagliflozin， donafenib， or lenvatinib on day 7 after the administration of the blank solvent； the rats in the pretreatment groups were given the pretreatment drug by gavage for 7 consecutive days， followed by a single dose of drug combination on day 7 after administration of the pretreatment drug. Blood samples were collected at different time points， and plasma was separated to measure the concentration of each drug. A validated ultra-performance liquid chromatography-tandem mass spectrometry method was used to measure the plasma concentrations of donafenib， lenvatinib， and empagliflozin， and a non-compartmental model was used to calculate the main pharmacokinetic parameters of each drug （area under the plasma concentration-time curve ［AUC］， time to peak ［Tmax］， peak concentration ［Cmax］， and half-life time ［t1/2］）. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups.  Results  Compared with the empagliflozin group， the donafenib pretreatment+empagliflozin group had significant increases in the AUC0-t and AUC0-∞ of empagliflozin （P=0.011 and 0.008）， while the lenvatinib pretreatment+empagliflozin group had no significant change in the AUC of empagliflozin， with a slightly shorter Tmax （P=0.019）. Compared with the donafenib group， the empagliflozin pretreatment+donafenib group had significant increases in the AUC0-t and AUC0-∞ of donafenib （P=0.027 and 0.025）， as well as a significant increase in Cmax （P=0.015） and significant reductions in CLz/F and Vz/F （P=0.005 and 0.004）； compared with the lenvatinib group， the empagliflozin pretreatment+lenvatinib group had a reduction in the t1/2 of lenvatinib by approximately 5 hours （P=0.002）， with a trend of reduction in AUC0-t （P>0.05）.  Conclusion  Empagliflozin combined with donafenib may alter the pharmacokinetic parameters of both drugs， leading to a significant increase in the exposure levels of both drugs， and efficacy and adverse reactions should be monitored during co-administration. There are no significant changes in the exposure levels of empagliflozin and lenvatinib during co-administration.

     

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