Preliminary Study On The Tissue Distribution And Pharmacokinetic Of A New Compound-No.51

Cancer is a kind of disease threating human health seriously,whose incidence is on the rise in recent years.At present,the chemotherapy plays an important role in tumor treatment.Due to that the traditional antitumor drugs show resistance and side effects to the body’s normal tissue cells,so we urgently need new antitumor drugs with significant efficacy and little clinical side effects.The goal of our team is to synthesize new structure compound with antitumor activity.No.51 is one of the compounds we have synthesized with strong biological activity.Preliminary pharmacodynamics and the experiments in vitro have confirmed that the compound has certain activity of antitumor activity,and is expected to become a drug candidate.The method was successfully established for a pharmacokinetic study of the compound No.51 in rat after tail intravenous injection.The thesis mainly contains 4 parts as followed:Chapter 1:It provided a general overview for the present situation of the tumor,its pathogenesis and antitumor method.In addition,recent advance on the antitumor drugs and the significance of preclinical pharmacokinetic study were described.Chapter 2:A HPLC method for the determination of the compound No.51 in plasma samples was established and validated.This chapter focused on the specificity,linear range,recovery,repeatability,precision and stability under conditions that at room temperature,freeze-thaw,and-20℃refrigerated.The results showed that the experimental method was with a high specificity;linear range was 0.1～100μg/m L,limit of detection was 0.03μg/m L,limit of quantitation was 0.1μg/m L;the extraction recoveries of the concentrations of low,medium and high（0.2,5,50μg/m L）were 86.01%,89.87%and 92.21%with RSD less than4.05%;the RSD of repeatability were 2.12%,1.19%,1.70%;the method recoveries of the concentrations of low,medium and high levels were good;the RSD of repeatability of three days and daily repeatability were less than 3.83%;the stability of samples at room temperature,freeze-thaw stability and freeze stability in the concentration of low,medium and high levels were determined and the RSD were less than 8.76%.Chapter 3:A series of optimization experiments were carried out before the founded pharmacokinetic method.The stability test experiment of the compound No.51 determined the storage method of using water bath with a N₂evaporation to dry.Based on early pharmacodynamics experiment,long-term drug accumulate experiment,pharmacokinetic and tissue distribution experiment in mice were carried on.In addition,the chapter tried the pharmacokinetic experiment in rat with injecting into abdominal cavity.The two methods of abdominal cavity and blood collection from orbital venous plexus were achieved.Chapter 4:The pharmacokinetic experiment method of the compound No.51 in rats was established in the chapter.Polyoxyethylene castor oil-ethanol（1:1）was used as injection solvent.The experimental animal was rats.The blood drug concentration was determined and blood samples were collected from the orbital venous plexus before and after injected into tail intravenous by single dosing at 0.083,0.33,0.67,1,1.5,2,4,8 and 12 h.Then the concentration-time curve was ploted.The pharmacokinetic parameters of the compound of No.51 were as follows:t_1/2=4.70 h,AUC_0-t=9.47μg·h/m L,AUC_0-∞=9.96μg·h/m L,MRT=1.40 h,L=50.2 m L/min/kg,Vz=20.4 L/kg。...