Effect Of Chrysosplenetin On Pharmacokinetics Of Artemisinin

Artemisinin a sesquiterpene lactone endoperoxide is widely used as antimalarial drug for its rapid onset of action and little resistance.However,oral formulations of artemisinin are absorbed incompletely,which is one of the reasons for recrudescences.To slow down the incidence of antimalarial drug resistance,the WHO specifically advocated the use of artemisinin-based combination therapy as the standard policy in the treatment of malaria.Chrysosplenetin is a o-methylated flavonol.In this work,a Artemisinin-Chrysosplenetin combination was administered to evaluate the influence of Chrysosplenetin on the pharmacokinetics of Artemisinin,and then provide guidance for the mechanism study of drug combination of CHR with Artemisinin.Aim:To study the influence of Chrysosplenetin(CHR)on the pharmacokinetics of Artemisinin(QHS),then provide guidance for the drug combination of CHR with Artemisinin and the mechanism.Methods:To evaluate the pharmacokinetics of QHS in rats,a UHPLC-tandem mass spectrometric(LC/MS/MS)method for the determination of QHS in rat plasma was developed and validated.An aliquot(10 μL)was injected into a Shim-pack XR-ODS column(2.0mmid×100mm),which were kept at 30℃.The mobile phase consisted of acetonitrile and 0.1%formic acid in 10mM aqueous ammonium acetate(85:15,v/v).The flow rate was 0.3ml·min-1.For detection,a Sciex API 4000 LC/MS/MS instrument with an electrospray ionization(ESI)TurboIonSpray inlet in the positive ion multiple reaction monitoring(MRM)mode was used to monitor product ions of m/z 300.1-283.2 for QHS and m/z 316.2-163.0 for artemether,the internal standard(IS).The standard curve was linear(r>0.99)over the QHS concentration range of 0.2～200.0ng·ml-1 in plasma.The lower limit of quantification of this method is 0.2 ng·ml-1 for QHS in 100μl of plasma,which offered a satisfactory sensitivity for the determination of QHS.The method is stable,cheap and convenient,and is proved to be suitable for investigation of the pharmacokinetics of QHS.Rats were randomly divided to QHS group and QHS-CHR combination group including CHR low-dose group,middle-dose group and high-dose group,and were administrated by QHS for 5 days and QHS-CHR for 5 days.On the 5th day,the blood samples were obtained soon after administration through extirpating the eyeballs at a series of time-points.The influence of CHR on the pharmacokinetics of QHS was reflected by the changes of pharmacokinetic parameters of QHS.Results:The Cmax of QHS of rats in control group and text group respectively were:51.58±9.47、84.76±19.52、85.22±29.56、63.16±16.50ng·ml-1.The t1/2 were:243±58、243±108、349±117,312±153min.The AUC were:23443±1955、33658±6065、32859±4596、30282±3293min·mg·L-1.There was a statistically significant difference in the AUC of artemisinin between two groups analyzed by t-text.Conclusion:The results show that the combination of QHS and CHR increases the relative bioavailability ofartemisinin.