Effect and mechanism of ertugliflozin on pharmacokinetic of sorafenib and donafenib in rats
- VernacularTitle:艾托格列净对索拉非尼和多纳非尼在大鼠体内药动学的影响及机制研究
- Author:
Yanru DENG
1
,
2
,
3
;
Zhi WANG
1
,
3
;
Gexi CAO
1
,
2
,
3
;
Bin YAN
1
,
2
,
3
;
Ying LI
1
,
3
;
Zhanjun DONG
1
,
2
Author Information
1. Dept. of Pharmacy，Hebei General Hospital，Shijiazhuang 050051，China
2. School of Pharmacy，Hebei Medical University，Shijiazhuang 050051，China
3. Hebei Key Laboratory of Clinical Pharmacy，Shijiazhuang 050051，China
- Publication Type:Journal Article
- Keywords:
ertugliflozin;
sorafenib;
donafenib;
pharmacokinetics;
UPLC-MS/MS
- From:
China Pharmacy
2025;36(7):826-831
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE To investigate the effects of ertugliflozin on pharmacokinetic of sorafenib and donafenib in rats and explore the mechanism. METHODS Twenty-four male SD rats were randomly divided into four groups， with 6 rats in each group. Groups A and B were respectively gavaged with 0.5% sodium carboxymethyl cellulose solution and ertugliflozin （1.5 mg/kg） for 7 consecutive days， and both were given sorafenib （100 mg/kg） on the 7th day. Groups C and D were administered intragastrically in the same way as those in Groups A and B， respectively， for the first 7 days； after the drug administration on the 7th day， all rats in Groups C and D were further gavaged with donafenib （40 mg/kg）. Blood samples were collected at different time points before and after administration of sorafenib or donafenib， the concentrations of sorafenib in plasma of rats in groups A and B and donafenib in groups C and D were determined by UPLC-MS/MS method. The pharmacokinetic parameters were calculated by DAS 2.1.1 software. Six additional rats were randomly divided into blank control group and ertugliflozin group， with three rats in each group. Blank control group was given 0.5% sodium carboxymethyl cellulose intragastrically， while rats in ertugliflozin group were given ertugliflozin （1.5 mg/kg） once a day for 7 consecutive days. After the last administration， the mRNA expression levels of uridine diphosphate glucuronosyl transferase 1A7 （UGT1A7）， breast cancer resistance protein （BCRP）， and P-glycoprotein （P-gp） in the liver and small intestine tissues of the rats were detected. RESULTS Compared with group A， the AUC0-t， AUC0-∞， cmax， tmax， MRT0-t and MRT0-∞ of sorafenib in group B were decreased significantly， while CL and V were increased significantly. Compared with group C， the AUC0-t， AUC0-∞ ， tmax， cmax and MRT0-t of Δ donafenib in group D were decreased significantly， while V and CL were increased significantly （P＜0.05）. mRNA expression of UGT1A7， P-gp and BCRP in the liver tissue and small intestine of rats were not significantly affected after intragastric administration of ertugliflozin for 7 consecutive days. CONCLUSIONS Ertugliflozin can affect the pharmacokinetics of sorafenib and donafenib in rats and decrease the plasma exposure of them significantly. However， its mechanism of action may not be through the regulation of related metabolic enzymes and transporters. When using drugs in combination clinically， one should be vigilant about the potential for disease progression due to poor therapeutic effects.
