Drug metabolome of the Simvastatin formed by human intestinal microbiota in vitro

Anna-Marja Aura (Corresponding Author), Ismo Mattila, Tuulia Hyötyläinen, Peddinti Gopalacharyulu, Catherine Bounsaythip, Matej Oresic, Kirsi-Marja Oksman-Caldentey

    Research output: Contribution to journalArticleScientificpeer-review

    42 Citations (Scopus)


    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*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 ß-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.
    Original languageEnglish
    Pages (from-to)437-446
    JournalMolecular bioSystems
    Issue number2
    Publication statusPublished - 2011
    MoE publication typeA1 Journal article-refereed


    Dive into the research topics of 'Drug metabolome of the Simvastatin formed by human intestinal microbiota in vitro'. Together they form a unique fingerprint.

    Cite this