Comparative Pharmacokinetic Study Of Azilsartan Medoxomil And Azilsartan In Human

PURPOSEIn this study,a simple and rapid liquid chromatography-tandem mass spectrometry(LC-MS/MS)method was developed and validated for the determination of azilsartan(AZL)and its metabolite M-Ⅰ and M-Ⅱ in human plasma.The method was successfully applied to a clinical pharmacokinetic study that compares differences of pharmacokinetics after an oral administration of azilsartan tablet and azilsartan medoxomil(AZM)tablet.METHODMass spectrometry detection was performed on a QTRAP 5500 mass spectrometer equipped with an ESI source operated in the positive ionization mode.Under Q1 full scan mode,strong signals of protonated molecular[M+H]+ ions of AZL,M-Ⅰ,M-Ⅱand IS were found.Different CE values were tested to produce the most abundant and stable product ions.As a result,the ion transitions of m/z 457.3→233.1,m/z 415.3→192.1,m/z 429.3→251.1 and m/z 408.3→235.1 were therefore selected for MRM of AZL,M-Ⅰ,M-Ⅱ and IS,respectively.Agilent Eclipse Plus C18(2.1×50 mm I.D.,5 μm,Agilent Technologies Inc.,USA)presented a good resolution and excellent peak shapes for analytes and IS when a gradient elution with methanol and 5mM ammonium acetate was operated at a flow rate of 0.4 mL/min.Protein precipitation was used to purified plasma samples for the reasons of sample process.Methanol at a certain volume of 600 μL was chosen as protein precipitant due to its low solvent effect and preferable precipitation efficiency.After precipitation,the supernate was diluted by mobile phase to reduce matrix effect before injected into the LC-MS/MS system.The concentration of AZL,M-Ⅰ and M-Ⅱ in human plasma samples was measured.The concentration-time profiles of analytes were drawn and pharmacokinetic parameters such as peak concentration(Cmax),peak time(Tmax),half life(ti/2),area under concentration-time curve(AUC0-t)and area under concentration-time curve(AUC0-∞)were caculated and analyzed in order to evaluate the pharmacokinetic characteristics.RESULTSA rapid and sensitive LC-MS/MS method for the determination of AZL,M-1 and M-II in human plasma has been developed and validated.The method has advantages on small volume of sample,simple sample preparation with high recovery,short analytical run time and high sensitivity.No significant endogenous interference was observed in the blank sample.The accuracy and the intra-and inter-run precision were corresponded to the requirement.The samples were proved to be stable during storage,transportation and analysis.The method was shown to be useful for the further clinical pharmacokinetic studies.Relative to AZL group,AZL and M-II AUC0-t,AUC0-∞,and Cmax increased obviously in AZM group.That means prodrugs AZM has higher absorption degree than AZL and increased bioavailability.In summary,this study provides the scientific basis for the further clinical research of AZM tablet.