Effect of amlodipine and levamlodipine on the pharmacokinetics of lenvatinib in rats and related mechanisms
- VernacularTitle: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
- Author:
Bin YAN
1
,
2
,
3
;
Gexi CAO
;
Yanru DENG
;
Ying LI
;
Zhanjun DONG
;
Wanjun BAI
Author Information
- Keywords: Carcinoma,Hepatocellular; Rats,Sprague-Dawley; Amlodipin; Lenvatinib
- From: Journal of Clinical Hepatology 2024;40(11):2246-2252
- CountryChina
- Language:Chinese
- 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 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.
