| Icotinib is the first self-developed small molecule drug in China for treatment of non-small cell lung cancer.Considering that patients with lung cancer are frequently prescribed multiple medications,it is important to determine whether the coadministration of icotinib with other drugs would result in a drug-drug interaction?DDI?.Part one Determination of icotinib in plasma by UPLC-MS/MSObjective:The purpose of this study was to develop an UPLC-MS/MS method for determination of icotinib concentration in plasma.Methods:Protein precipitation with acetonitrile was utilized for plasma sample preparation.The analytes were separated on a kinetex C188 column using 10 mM ammounium acetate containing 0.2%formic acid and methanol?30:70?as mobile phase.The gradient elution procedure was optimized as follows:0.01-1min,0.2mlˇmin-1;1-2min,0.2-0.4mlˇmin-1;2-3.5min,0.4mlˇmin-1;3.5-3.51min,0.4-0.2mlˇmin-1;3.51-4.5min,0.2mlˇmin-1.The LC system was connected to mass spectrometer via electrospray ionization?ESI?interface operated in positive ion mode.The mass monitoring was operated in multiplereaction monitoring?MRM?mode.Precursor-to-product transitions were m/z 392.2?303.7 for icotinib,and m/z 248.0?121.1 for internal standard tinidazole.Results:The assay showed good linearity over the concentration ranges of 1-1000 ng/ml for icotinib with correlation coefficients more than 0.997.The intra-and inter-day precisions?RSD,%?were no more than 10.47%.The results demonstrated that the stabilitis,matrix effect,extraction recovery and dilution stability were all under the described conditions.Conclusions:A simple and sensitive UPLC-MS/MS method was developed and validated for dertermination of icotinib in plasma.Part two Effects of itraconazole,simvastatin and carbamazepine on the pharmacokinetics of icotinib in ratsObjective:The coadministration drugs could decrease or increase the activity of CYP-mediated isoenzyme,which might influence the pharmacoki-netics of icotinib.This study was conducted to identify the DDI effects of itraconazole,simvastatin and carbamazepine on the pharmacokinetics of icotinib in rats.Methods:32 healthy male SD rats were randomly divided into 4 groups,the control group?icotinib alone group?,group A?itraconazole+icotinib combination group?,group B?simvastatin+icotinib combination group?,and group C?carbamazepine+icotinib combination group?.Samples were collected before icotinib administration and 0.25,0.5,1,1.5,2,3,5,8,10,24 and 48hours after dosing.Pharmacokinetic parameters of each medical group were calculated by noncompartmental analysis using the Drug and Statistics Software?DAS?3.0.All data were subjected with the Statistical Package for Social Sciences?SPSS 21.0?.Results:As compared with rats treated with icotinib alone,there were no significant differences in the rats pretreated with itraconazole and simvastatin about AUC?0-t?,AUC?0-??,Lambdaz,MRT?0-t?,MRT?0-??,t1/2,Cl,Vd,Tmax,Cmaxax and Clast.The pharmacokinetic parameters of AUC?0-t?,AUC?0-??,Cmax,Vd and CL showed significant differences in the carbamazepine group,which decreases of 58.37%,57.84%,55.81%in AUC?0-t?,AUC?0-??and Cmax,and increases of 1.79-,2.39-folds in CL,Vd respectively;compared with control group.Conclusions:Itraconazole and simvastatin had no significant effect on the pharmacokinetic parameters of icotinib in rats.Coadministration of icotinib with carbamazepine in rats decreased the plasma concentration and bioavailability,and increased Vd and CL. |
PDF Full Text Request