Drug metabolome of the Simvastatin formed by human intestinal microbiota in vitro
Drug metabolome of the Simvastatin formed by human intestinal microbiota in vitro
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DOI：
10.1039/c0mb00023j
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发表时间：
2011-01-01
影响因子：
--
通讯作者：
Oksman-Caldentey, Kirsi-Marja
中科院分区：
文献类型：
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作者：
Aura, Anna-Marja;Mattila, Ismo;Oksman-Caldentey, Kirsi-Marja
人类结肠含有多种微生物种群，有助于食物成分的降解和代谢。结肠中的药物代谢通常知之甚少。代谢组学技术和体外结肠模型现在可以提供结肠代谢背景下药物代谢物的详细表征。本研究的目的是利用体外无氧人结肠模型结合系统生物学平台，排除宿主肝脏和肠上皮细胞的代谢，鉴定辛伐他汀（SV）的新型药物代谢产物。综合二维气相色谱-飞行时间质谱（GC x GC-TOFMS）用于代谢组学分析。在活性粪便悬浮液中显示最显著差异的代谢物在SV片段化方面进行了阐明，并与对照组进行了比较：无活性悬浮液或含有SV的缓冲液，或仅含有活性悬浮液。最后，研究了选定代谢物的时程。我们的数据表明，SV是由SV骨架的甲基丁酸水解裂解降解。代谢涉及二甲基丁酸的脱甲基化、羟基化/脱羟基化和β-氧化，导致产生2-羟基异戊酸（3-甲基-2-羟基丁酸）、3-羟基丁酸和乳酸（2-羟基丙酸），最后庚酸再环化（可能脱酯化和裂解甲基吡喃臂），产生环己烷羧酸。我们的研究阐明了SV的结肠微生物代谢途径，并证明了体外结肠模型和代谢组学对从药物反应谱中发现新型药物代谢物的适用性。
The human colon contains a diverse microbial population which contributes to degradation and metabolism of food components. Drug metabolism in the colon is generally poorly understood. Metabolomics techniques and in vitro colon models are now available which afford detailed characterization of drug metabolites in the context of colon metabolism. The aim of this work was to identify novel drug metabolites of Simvastatin (SV) by using an anaerobic human in vitro colon model at body temperature coupled with systems biology platform, excluding the metabolism of the host liver and intestinal epithelia. Comprehensive two-dimensional gas chromatography with a time-of-flight mass spectrometry (GC x GC-TOFMS) was used for the metabolomic analysis. Metabolites showing the most significant differences in the active faecal suspension were elucidated in reference with SV fragmentation and compared with controls: inactive suspension or buffer with SV, or with active suspension alone. Finally, time courses of selected metabolites were investigated. Our data suggest that SV is degraded by hydrolytic cleavage of methylbutanoic acid from the SV backbone. Metabolism involves demethylation of dimethylbutanoic acid, hydroxylation/dehydroxylation and beta-oxidation resulting in the production of 2-hydroxyisovaleric acid (3-methyl-2-hydroxybutanoic acid), 3-hydroxybutanoic acid and lactic acid (2-hydroxypropanoic acid), and finally re-cyclisation of heptanoic acid (possibly de-esterified and cleaved methylpyranyl arm) to produce cyclohexanecarboxylic acid. Our study elucidates a pathway of colonic microbial metabolism of SV as well as demonstrates the applicability of the in vitro colon model and metabolomics to the discovery of novel drug metabolites from drug response profiles.