Zidovudine azido-reductase in human liver microsomes: Activation by ethacrynic acid, dipyridamole, and indomethacin and inhibition by human immunodeficiency virus protease inhibitors
Zidovudine azido-reductase in human liver microsomes: Activation by ethacrynic acid, dipyridamole, and indomethacin and inhibition by human immunodeficiency virus protease inhibitors
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DOI：
10.1128/aac.42.7.1654
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发表时间：
1998-07-01
影响因子：
4.9
通讯作者：
Inaba, T
中科院分区：
文献类型：
--
作者：
Fayz, S;Inaba, T
AZT(齐多夫定，3‘-叠氮基-3’-脱氧胸苷)虽然主要代谢为AZT-葡萄糖醛酸苷，但也可通过叠氮还原为胺而代谢为3‘-氨基-3’-脱氧亚胺(AMT)，但髓毒性代谢物AMT的形成尚未得到很好的表征，但抑制AMT的形成将具有治疗意义，本研究的目的是寻找抑制AMT形成的化合物。利用厌氧条件下的人肝微粒体和[2-C-14]AZT，用放射薄层层析法估算AZT叠氮还原酶的K-m值为2.2~3.5 mM(n=3)，氧气完全抑制这种NADPH依赖的还原。在测试的28个化合物中，有13个化合物抑制AMT的形成。除细胞色素P3A4抑制剂酮康唑、氟康唑、吲地那韦、利托那韦和沙奎那韦外，美曲拉酮还能强烈抑制AMT的形成。一个意想不到的发现是，在乙炔酸、双嘧达莫或消炎痛的存在下，AMT的形成增加了两倍多，这种有毒代谢产物形成霉菌的激活阻碍了药物治疗。
AZT (zidovudine, 3'-azido-3'-deoxythymidine), although metabolized primarily to AZT-glucuronide, is also metabolized to 3'-amino-3'-deoxythmidine (AMT) by reduction of the azide to an amine, The formation of the myelotoxic metabolite AMT has not been well characterized, but inhibition of AMT formation would be of therapeutic benefit, The aim of this study was to identify compounds that inhibit AMT formation. Using human liver microsomes under anaerobic conditions and [2-C-14]AZT, K-m values of AZT azido-reductase, estimated by radio-thin-layer chromatography, were 2.2 to 3.5 mM (n = 3), Oxygen completely inhibited this NADPH-dependent reduction. Thirteen of the 28 compounds tested inhibited the formation of AMT. In addition to the CYP3A4 inhibitors ketoconazole, fluconazole, indinavir, ritonavir, and saquinavir, metyrapone strongly inhibited AMT formation. An unexpected finding was the more-than-twofold increase in AMT formation in the presence of ethacrynic acid, dipyridamole, or indomethacin, Such activation of toxic metabolite formation mould impair drug therapy.