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首页> 外文期刊>Journal of chromatography, A: Including electrophoresis and other separation methods >Investigation of the species-dependent in vitro metabolism of BAL30630 by stable isotope labeling and isotope exchange experiments analyzed by capillary liquid chromatography coupled to mass spectrometry
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Investigation of the species-dependent in vitro metabolism of BAL30630 by stable isotope labeling and isotope exchange experiments analyzed by capillary liquid chromatography coupled to mass spectrometry

机译：通过稳定的同位素标记和毛细管液相色谱-质谱联用的同位素交换实验研究BAL30630的物种依赖性体外代谢

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摘要

The in vitro metabolic profile of BAL30630, an antifungal piperazine propanol derivative, which inhibits the 1,3-beta-D-glucansynthase, was investigated by incubation with microsomes of several species and with rat hepatocytes. For the spotting of the metabolites, mixtures of BAL30630 with a stable isotope (deu_terium) labeled analogue were incubated. The metabolic pattern comprises several oxidized metabolites. Based on isotope exchange experiments, their structures could be assigned to epoxide- and hydroxylatecl metabolites. In hepatocyte incubations, several glucuronides formed from these oxidized metabolites could be observed. From the analysis of the metabolic pattern in microsomes, products of carbamate hydrolysis were characterized. This hydrolysis was highly species dependent. In activated incubations and in rat hepatocytes, those metabolites were further oxidized. In incubations without NADPH activation, the resulting hydrolytic metabolites could be enriched without the subsequent oxidation. Final structural elucidation of the metabolites was performed using accurate mass determination and isotope exchange experiments, in which incubations were analyzed by deuterium exchange and capillary HPLC-QTof-MS and MS/MS. The use of non-radioactive, stabile isotope labeled drug analogues in combination with isotope exchange studies was essential in particular for a defined assignment of the functional groups in the structures of the investigated metabolites.
机译：通过与几种物种的微粒体和大鼠肝细胞孵育，研究了抑制1,3-β-D-葡聚糖合酶的抗真菌哌嗪丙醇衍生物BAL30630的体外代谢谱。为了发现代谢物，将BAL30630与稳定同位素（氘）标记的类似物的混合物进行孵育。代谢模式包括几种氧化代谢产物。根据同位素交换实验，它们的结构可以分配给环氧和羟基代谢物。在肝细胞温育中，可以观察到由这些氧化代谢产物形成的几种葡糖醛酸苷。通过微粒体中代谢模式的分析，表征了氨基甲酸酯水解产物。该水解高度依赖于物种。在激活的温育和大鼠肝细胞中，这些代谢产物被进一步氧化。在没有NADPH活化的培养中，所得的水解代谢产物可以富集而无需随后的氧化。使用精确的质量测定和同位素交换实验对代谢物进行最终的结构解析，其中通过氘交换，毛细管HPLC-QTof-MS和MS / MS分析了孵育情况。非放射性的，稳定的同位素标记的药物类似物与同位素交换研究相结合的使用是必不可少的，特别是对于所研究代谢物结构中官能团的明确分配而言。

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