Preclinical Pharmacokinetics Of A New Anticancer Drug Of Tyrosine-kinase Inhibitor

Objective:According to the pharmacokinetics studies of NCE1407 in SD rat and Beagle dog after administration.This experiment aimed to provide reliable preclinical pharmacokinetic data for the further research by pharmacokinetic parameters,plasma protein and tissue distribution.Method:Pharmacokinetics of NCE1407 in plasma of healthy SD rats and Beagle dogs were studied in five groups:intragastric administration of low,medium and high,intragastric administration continuous for 7 days and intravenous,respectively.Drug concentration of plasma which collected at different time point was detected by LC-MS/MS.Tissue distribution in SD rats was studied by detected concentrations of NCE1407 in tissues after homogenate.Tissue samples were collected at 0.5 h,4 h,24 h and 48 h after intragastric administration of medium dose of NCE1407.Plasma protein binding studies were performed in different plasma of SD rats,ICR mice,Beagle dogs,and healthy people.The accuracy of the equilibrium dialysis method was verified by positive control group of propranolol hydrochloride and naproxen.The sample of NCE1407 was collected from plasma side and buffer side,respectively,in the low and high concentration group.The samples were analyzed through LC-MS/MS in this paper.The pharmacokinetic parameters were calculated by using WinNonlin 6.3 according to the quantitative analysis data.Result:Good linearity of NCE1407 was achieved over the range of 0.2—500 ng/mL.The endogenous substance in plasma did not interfere with the determination of NCE1407.The validated method was applied to in vivo drug analysis.In the dose range Cmax of NCE1407 was in a dose-dependent manner.AUC0-72h in SD rats in the body with a slight increase in dose and Tmax has a tendency to shorten.AUC0-72 in Beagle dogs with dose proportional increase and Tmax no significant difference.After multiple dosing,AUC and accumulation factors in SD rats and Beagle dogs were increased,and the bioavailability was 55.0%and 64.0%,respectively.Plasma protein binding was determined by equilibrium dialysis method.According to the positive control group,the protein binding rates of NCE1407 in plasma of different species were all around 99%.Distribution of NCE1407 was found in the tissue distribution of the tissue.The drug concentration in the tissue was basically in parallel with the plasma treatment process,and there was no accumulation in the tissue.Conclusion:An accurate,reliable and suitable method for pharmacokinetic studies of NCE1407 was validated.The data from various researches was true,reliable and accurate.This experiment provided a reference for the futher study of NCE1407.