Investigation of drug-drug interactions between bentysrepinine and tenofovir disoproxil fumarate based on pharmacokinetic
Objective To establish LC-MS/MS methods for the analysis of tenofovir(TFV),bentysrepinine(Y101)and its metabolite M8.The drug-drug interactions between Y101 and tenofovir disoproxil fumarate(TDF)and its mechanism were studied by using the model of in vivo pharmacokinetics,renal excretion and in vitro uptake in kidney slices.Methods ① Pharmacokinetic experiments:SD male rats were randomly divided into three groups:rats were orally given Y101(60 mg·kg-1),TDF(30 mg·kg-1)or TDF(30 mg·kg-1)+Y101(60 mg·kg-1),respectively.Plasma concentrations of Y101,M8 and TFV were determined by LC-MS/MS methods,and pharmacokinetic parameters were calculated by Phenix WinNonlin with non-compartmental analysis.② Renal excretion experiments:SD male rats were randomly divided into three groups:Rats via tail vein were injected with Y101(25 mg·kg-1),TDF(30 mg·kg-1)or TDF(30 mg·kg-1)+Y101(25 mg·kg-1),respectively.The concentrations of Y101,M8 and TFV in urine samples were determined by LC-MS/MS methods,and the cumulative excretion rates of drugs and their metabolites were calculated.③ Kidney slices experiments:Rat kidney slices were incubated in buffer containing M8(5.0 μmol·L-1),TFV(10 μmol·L-1),TFV(10μmol·L-1)+Y101(2.0 μmol·L-1)or TFV(10 μmol·L-1)+M8(5.0 μmol·L-1)for a certain period of time,respectively.The samples were collected and properly treated,and then the renal uptakes of TFV,Y101 and M8 were determined by LC-MS/MS methods.Results ① Pharmacokinetic experiments:A full validation of TFV and a partial validation of Y101 and M8 were carried out.These results showed that the LC-MS/MS methods were highly specific and sensitive.The concentrations of TFV,Y101 and M8 in rat plasma were determined by validated LC-MS/MS methods.It was found that compared with the Y101 or TDF treatment group,the area under the curve(AUC0-t and AUC0-∞)of TFV,Y101 and M8 in rat plasma increased significantly and the plasma clearance rate(CLP)decreased significantly in the group of TDF+Y101.② Renal excretion studies:The results showed that the cumulative urinary excretion of TFV and M8 in the TDF+Y101 group was significantly lower than the Y101 or TDF alone group.③ Kidney slices experiments:Compared with the TFV or M8 alone group,the uptakes of TFV or M8 decreased significantly in the TFV+M8 group.Conclusion TFV and M8 may have an impact on the blood concentrations and renal excretion of TFV and M8 through competitive inhibition of OAT3,suggesting that the dose needs to be adjusted in clinical combination.
万方数据
