Effects Of Simvastatin And Itraconazole On The Pharmacokinetics Of Erlotinib In Rats

Erlotinib,simvastatin and itraconazole are commonly used in the treatment of non-small cell lung cancer clinical,fall hematic fat and drug resistance to fungal infection.They have competitive relations of the same metabolic enzyme CYP3A4,and itraconazole is the inhibitor of CYP3A4enzyme preparations.This experiment through the establishment of LC-MS/MS determination of rats it for method,a preliminary investigation of simvastatin and itraconazole for it in rats for pharmacokinetic effects,so as to provide reference for clinical rational drug use.Part one LC-MS/MS method for the determination of erlotinibblood concentration in ratsObjective:Establish a method of liquid chromatography tandem mass spectrometry?LC-MS/MS?to determine the concentration of erlotinib in rats,which could provide reference for investigating the effects of simvastatin and itraconazole on the pharmacokinetics of erlotinib in rats.Methods:1 Chromatographic and mass spectrometric conditionsColumn:Kinetex C18?100×2.1 mm,2.6?m?;Column temperature:50?;Autosampler temperature:4?;The mobile phase:0.1%formic acid,10 mM ammonium acetate?A?-0.1%formic acid,methanol?B?;Gradient elution,Injection volume:3?L;Ion source:ESI;Ion mode:MRM;Detection mode:positive ions;Erlotinib quantitative ion pair:394.2/336.0 m/z;Internal standard tinidazole quantitative ion pair:248.0/121.1 m/z.2 Plasma samples were treated with acetonitrile protein precipitation.Results:The concentration range of erlotinib was 5-1000 ng/mL.The standard curve equation:Y=0.00553X+0.0273,r=0.9943,the lower limit of quantitation was 5 ng/mL.All the results of the methodology were in accordance with the requirements of the 2015 edition of the Chinese pharmacopoeia.Part two Effects of simvastatin and itraconazole on the pharmacokinetics of erlotinib in ratsObjective:On the basis of the previous LC-MS/MS method to accurately determine the concentration of erlotinib in rats,this part would investigate the effects of simvastatin and itraconazole on the pharmacokinetics of erlotinib in rats,which could provide reference for rational clinical use of erlotinib.Methods:Healthy SD rats 24,male,weight:220²60 g,were randomly divided into three groups?n=8?.For the control group?erlotinib single drug group?,the experimental group A?erlotinib+simvastatin pills combined drug group?and group B?erlotinib+itraconazole capsule combined drug group?.Dosage of administration:erlotinib tablet was 13.5 mg/kg,simvastatin tablet for 2 mg/kg,itraconazole capsule for 15 mg/kg.Take blood from the canthus at different time points before and after administration in rats.The plasma concentration of erlotinib in rats was determined by the LC-MS/MS method.The data of erlotinib blood concentration in three groups of rats were treated with DAS 3.0 software.And SPSS 20.0 software was used to compare the main pharmacokinetic parameters of each group..Results:Group A?erlotinib+simvastatin pills combined drug group?:Non-compartment model parameters of AUC_?0-t?,AUC_?0-??,C_max,t_max,t_1/2,Vd,CL,MRT_?0-t?,MRT_?0-??,C_last had no difference,compared with control group;Group B?erlotinib+itraconazole capsule combined drug group?:Non-compartment model parameters of AUC_?0-t?,AUC_?0-??,C_max,t_1/2,Vd,CL,MRT_?0-t?,MRT_?0-??,C_last had no difference,compared with control group.But t_maxax was significantly decreased.Conclution:1.The LC-MS/MS method established in this study was used to determine the plasma concentration method in rats with a high sensitivity,strong specificity and wonderful accuracy.It was applicable to the determination of erlotinib plasma concentration in rats.2.Simvastatin had no significant effect on the pharmacokinetic parameters of erlotinib in rats.However,itraconazole had a certain effect on the t_maxax of erlotinib in rats and had no significant effect on other parameters.