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

28 Citations (Scopus)

Abstract

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
Volume7
Issue number2
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

Fingerprint

Simvastatin
Metabolome
Colon
Metabolomics
Pharmaceutical Preparations
Suspensions
simvastatin acid
Heptanoic Acids
Lactic Acid
Acids
Systems Biology
Drug Discovery
Cyclization
Intestinal Mucosa
Hydroxylation
Body Temperature
Gas Chromatography
Gastrointestinal Microbiome
In Vitro Techniques
Mass Spectrometry

Cite this

Aura, Anna-Marja ; Mattila, Ismo ; Hyötyläinen, Tuulia ; Gopalacharyulu, Peddinti ; Bounsaythip, Catherine ; Oresic, Matej ; Oksman-Caldentey, Kirsi-Marja. / Drug metabolome of the Simvastatin formed by human intestinal microbiota in vitro. In: Molecular bioSystems. 2011 ; Vol. 7, No. 2. pp. 437-446.
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abstract = "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.",
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Aura, A-M, Mattila, I, Hyötyläinen, T, Gopalacharyulu, P, Bounsaythip, C, Oresic, M & Oksman-Caldentey, K-M 2011, 'Drug metabolome of the Simvastatin formed by human intestinal microbiota in vitro', Molecular bioSystems, vol. 7, no. 2, pp. 437-446. https://doi.org/10.1039/C0MB00023J

Drug metabolome of the Simvastatin formed by human intestinal microbiota in vitro. / Aura, Anna-Marja (Corresponding Author); Mattila, Ismo; Hyötyläinen, Tuulia; Gopalacharyulu, Peddinti; Bounsaythip, Catherine; Oresic, Matej; Oksman-Caldentey, Kirsi-Marja.

In: Molecular bioSystems, Vol. 7, No. 2, 2011, p. 437-446.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Aura, Anna-Marja

AU - Mattila, Ismo

AU - Hyötyläinen, Tuulia

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AU - Bounsaythip, Catherine

AU - Oresic, Matej

AU - Oksman-Caldentey, Kirsi-Marja

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AB - 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.

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DO - 10.1039/C0MB00023J

M3 - Article

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JO - Molecular bioSystems

JF - Molecular bioSystems

SN - 1742-206X

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Aura A-M, Mattila I, Hyötyläinen T, Gopalacharyulu P, Bounsaythip C, Oresic M et al. Drug metabolome of the Simvastatin formed by human intestinal microbiota in vitro. Molecular bioSystems. 2011;7(2):437-446. https://doi.org/10.1039/C0MB00023J