Pharmacokinetic interactions between donafenib and empagliflozin or henagliflozin , lenvatinib and empagliflozin or henagliflozin in rats

Abstract

Donafenib(DONA) and lenvatinib(LEN) are small-molecule tyrosine kinase inhibitors(TKI) that are used to treat advanced hepatocellular carcinoma(HCC).Empagliflozin and henagliflozin are sodium-glucose cotransporter 2(T2DM) inhibitors that are used to treat type 2 diabetes(T2DM).Empagliflozin and henaglifiozin are uridine diphosphate glucuronosyltransferase(UGT)1A9, Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)Donafenib is metabolized by UGT1A9 and is an inhibitor of UGT1A9 and lenvatinib is a substrate for P-gp and BCRP.T2DM is one of the risk factors for HCC progression, so the two drugs may be used in combination in clinical practice, but there is a lack of clear information about drug interactions. Therefore, the present study aimed to reveal the extent of drug interactions between donafenib, lenvatinib and empagliflozin and henagliflozin in rats and explore the possible mechanisms.Rats were divided into fourteen groups (n = 6) that received empaglifiozin(1,2),henagliflozin(3,4,)donafenib(5), lenvatinib(6), empaglifiozin and donafenib (7), hennagliflozin and donafenib (8), empaglifiozin and lenvatinib(9) ,henagliflozin and lenvatinib (10),donafenib and empaglifiozin (11), donafenib and henagliflozin (12),lenvatinib and empaglifiozin(13),lenvatinib and henagliflozin(14). The concentrations of drugs were determined by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The messenger RNA (mRNA) expressions were measured by quantitative RT-PCR. Multiple administration of empagliflozin reduced the area under the concentration-time curve (AUC0 − t and AUC0−∞) of donafenib by 33.46% and 32.7% respectively. The apparent clearance rate (CLz/F) and apparent volume of distribution (Vd/F) were reduced by 66.7% and 95.2%, respectively. The half-life (T1/2) was prolonged by 17.6%.Henagliflozin modest decreased donafenib AUC0 − t and AUC0−∞ by 27.8% and 26.9%. The CLz/F of donafenib was 2.6-fold compared to the control group.Multiple doses of donafenib caused empagliflozin to AUC0 − t and AUC0−∞ increased by 57.5%and58.5%. CLz/F were significantly decreased by 39.9% .The combination of multiple doses of donafenib increased the maximum plasma concentration (Cmax) of henagliflozin by 65.5%, AUC0 − t and AUC0−∞ by 177.0% and178.0%, respectively. CLz/F and Vz/F of hanagliflozin were decreased by 64.1% and 45.1%.Multiple administration of empagliflozin decreased the AUC0 − t and AUC0−∞ of lenvatinib by 18.7% and21.4%, respectively. CLz/F was accelerated by 30.0%. After multiple administration of constant gliflozin, the AUC0 − t and AUC0−∞ of lenvatinib decreased by 20.3% and 20.9%, respectively, and CLz/F increased by 1.30-flod.Multiple doses of lenvatinib had no significant effect on the pharmacokinetics of empagliflozin and henagliflozin.The pharmacokinetic results suggest that it is important to take special care of the interactions of these drugs in clinical applications.