Microbial production of phase I and phase II metabolites of midazolam
Microbial production of phase I and phase II metabolites of midazolam
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DOI：
10.3109/00498254.2011.622417
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发表时间：
2012-03-01
期刊：
影响因子：
1.8
通讯作者：
Azerad, Robert
中科院分区：
文献类型：
--
作者：
Marvalin, Cyrille;Denoux, Mireille;Azerad, Robert
1.咪达唑仑是一种有效的苯二氮卓类衍生物，也是细胞色素P3A4/3A5的典型底物，在人体内主要被代谢成1‘-羟基咪唑仑，然后作为相应的II相代谢物消除，即1’-O-β-D-葡萄糖醛酸衍生物。描述了一种利用真菌微生物球孢白僵菌对咪达唑仑的生物转化来替代目前多步合成1‘-羟基咪唑仑的高产率替代方法。相应的II相代谢物1‘-羟基咪唑仑-1’-O-β-D-葡萄糖醛酸苷是用链霉菌通过化学合成(3步，产率20%)或微生物葡萄糖醛酸化反应(一步，产率20%)得到的。努力工作。使用相同的链霉菌菌株可以直接和方便地从咪达唑仑本身合成相同的葡萄糖醛酸偶联物，产率为17%。
1. Midazolam, a potent benzodiazepine derivative and a typical substrate of CYP3A4/3A5, is essentially metabolized in human into 1'-hydroxymidazolam, then eliminated as the corresponding phase II metabolite, the 1'-O-beta-D-glucuronide derivative.2. A high yield alternative to the current multistep synthesis of 1'-hydroxymidazolam is described, using a biotransformation of midazolam by a fungal microorganism, Beauveria bassiana.3. The corresponding phase II metabolite, 1'-hydroxymidazolam-1'-O-beta-D-glucuronide, has been then prepared by chemical synthesis (3 steps, 20% yield), or by microbial glucuronidation (one step, 20% yield) using a Streptomyces sp. strain.4. The use of the same Streptomyces strain allows a direct and expeditive synthesis of the same glucuronide conjugate from midazolam itself in an advantageous 17% yield.