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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.
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 CM3600 XP. After proper treatment, the radioactivity level of each tissue and region of interest in the slices were obtained by phosphorus imaging technology.
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.
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.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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