The Study On Preclinical Pharmacokinetics Of Rhap And XC302 With Isotopic Tracer Method

Objective This thesis is designed to finish the preclinical pharmacokinetics study of xc302 and rhap with isotopic tracer method, and provide research base for its clinical study.Method①γ-counter and liquid scintillation analyzer were employed to determinate rhap and xc302 in biological matrix, and then pharmacokinetic parameters were calculated.②By using sample oxidizer in order to avoid quench effect.③Whole body autoradiography and tissue distribution were used together in order to make the result more reliability.ResultsIn study of rhap, rhap widely distributed and rapidly diminished in most tissues. Kidney contained the highest radioactivity in organs and the distribution of rhap to fat was minimal. Concentration was always higher in kidney which suggested that major elimination route is urinary excretion. Concentration in fat, muscle and brain is lower suggest that rhap is difficult to get into fat tissues After a single iv bolus administration, the t_1/2 is 2.8±1.2h.The cumulative excretion of rhap reached 71.8±2.2% of the administered radioactivity at 48 h and 94.7±1.5% at 120 h. Urinary excretion was the dominant route of elimination following iv administration, as 80.6±1.5 % and 14.1±1.0 % of administered radioactivity were recovered in urine and feces, respectively, in intact rats over 120 h.In study of xc302, most tissues reached the highest concentration at 3h after administration, then descended, most tissue reached the lowest concentration at 24 after administration, most of the drug and metabolite had excreted. With time prolong, the concentration of tumor descended slowly compared with other tissues which suggested xc302 has the target effect of tumor. After a single i.g. administration, The cumulative bile excretion of xc302 reached 5.9±0.2% of the administered radioactivity at 48 h. The cumulative urinary and feces excretion of xc302 reached respectively 7.2±0.3% and 84.0±0.6% of the administered radioactivity at 264 h and above 80% at 36h. After administration, most of urinary and feces sample were metabolite. Percentage of plasma protein binding of xc302 was more than 90%, indicating that it had better be avoided using together with other drugs that were highly binded with plasma protein. By using liver microsome incubation, found two metabolites.Conclusion This thesis conducted preclinical pharmacokinetic study of xc302 and rhap, and it provides crucial information for its clinical research.