Noguchi T, Ichii S, Morisada S, Yamaoka T, Yanagi Y
Research Center, Sumitomo Pharmaceuticals Co., Ltd., Osaka.
Jpn J Cancer Res. 1998 Oct;89(10):1061-6. doi: 10.1111/j.1349-7006.1998.tb00497.x.
It has been reported that the 9-aminoanthracycline amrubicin shows good efficacy in human tumor xenograft models. We studied the disposition and metabolism of amrubicin in mice, in comparison with those of doxorubicin. Amrubicinol, a 13-hydroxy metabolite of amrubicin, which is 10 to 100 times more cytotoxic than amrubicin, was detected as a major metabolite in blood and tissues, and aglycones of amrubicin were also detected. A pharmacokinetic study revealed that amrubicin had a smaller distribution volume and a shorter half-life than doxorubicin. In several normal tissues, the levels of amrubicin and amrubicinol were lower than those of doxorubicin. In contrast, the tumor levels of amrubicinol in the mice treated with amrubicin were higher than those of doxorubicin in the mice treated with that drug, in tumors that are sensitive to amrubicin. These results suggest that the potent therapeutic activity of amrubicin is caused by the selective distribution of its highly active metabolite, amrubicinol, in tumors.
据报道，9-氨基蒽环类抗生素氨柔比星在人肿瘤异种移植模型中显示出良好的疗效。我们研究了氨柔比星在小鼠体内的处置和代谢，并与多柔比星进行了比较。氨柔比星醇是氨柔比星的13-羟基代谢产物，其细胞毒性比氨柔比星高10至100倍，被检测为血液和组织中的主要代谢产物，同时也检测到了氨柔比星的苷元。一项药代动力学研究表明，氨柔比星的分布容积比多柔比星小，半衰期比多柔比星短。在几个正常组织中，氨柔比星和氨柔比星醇的水平低于多柔比星。相反，在对氨柔比星敏感的肿瘤中，用氨柔比星治疗的小鼠体内氨柔比星醇的肿瘤水平高于用多柔比星治疗的小鼠体内多柔比星的肿瘤水平。这些结果表明，氨柔比星的强效治疗活性是由其高活性代谢产物氨柔比星醇在肿瘤中的选择性分布所引起的。
