应用整体自显影定量技术开展的单多次给药后大鼠组织分布比较研究

目的:应用整体自显影定量技术(QWBA),比较单次和重复多次给药后大鼠体内的组织分布情况,以指导人体放射性物质平衡试验设计.方法:按15 mg ? kg-1剂量,分别灌胃给予雄性Long-Evans(LE)大鼠0,7和14次的非放射性标记药物VPS-01(qd)24h后单次灌胃给予100 μCi/15 mg?kg-1的...

Tissue distribution by quantitative whole body autoradiography after single and repeated administration in rats

Objective: Tissue distribution after single and repeated doses in rats was compared by quantitative whole body autoradiography technique (QWBA) to guide the design of human radioactive mass balance study.Methods: Male Long Evans (LE) rats were given,by gavage,0,7 and 14 doses (once a day) of non-radiolabeled drug VPS-01,at 15 mg·kg^-1,followed by a single dose of [14C]VPS-01 at 100 μCi/15 mg·kg^-1,po,at 24 h post last non-radioactive dose (defined as 0 + 1,7 + 1 and 14 + 1 groups,respectively). And then,after 3,24,168 and 504 h of radiolabeled drug administration,one rat from each group was sacrificed and carcasses were collected and frozen immediately,followed by sliced using Leica CM3600XP. After proper treatment,the radioactivity level of each tissue and region of interest in the slices were obtained by phosphorus imaging technology. Results: The total radioactivity of VPS-01 and/or its related metabolites was observed bound to melanin. Compared with 0 + 1 group,the radiation concentration and exposure of rats in 7 + 1 group significantly reduced,and the maximum radiation dose of [14C]VPS-01 in humans could accordingly increase from 61. 6 μCi to 611 μCi. However,no significant difference of exposure was observed between 14 + 1 group and 7 + 1 group. Conclusion: Drugs with slow elimination due to tissue covalent binding are easy to result in high radiation exposure in the human body in the mass balance study. If the subjects are given non-radiolabeled drugs repeatedly for several times to reach a steady state in human body before a single dose of the 14C-drug is given,the radiation exposure of subjects can be significantly reduced,the optional range of human radiation dose can be increased,and the radioactivity in the circulating blood will be increased,facilitating metabolite identification.