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Gut microbiota metabolizes nabumetone in vitro: Consequences for its bioavailability in vivo in the rodents with altered gut microbiome
L. Jourova, P. Anzenbacher, Z. Matuskova, R. Vecera, J. Strojil, M. Kolar, M. Nobilis, P. Hermanova, T. Hudcovic, H. Kozakova, M. Kverka, E. Anzenbacherova,
Language English Country Great Britain
Document type Journal Article, Video-Audio Media
- MeSH
- Anaerobiosis MeSH
- Anti-Bacterial Agents pharmacology MeSH
- Anti-Inflammatory Agents, Non-Steroidal metabolism pharmacokinetics MeSH
- Biological Availability MeSH
- Imipenem pharmacology MeSH
- Naphthaleneacetic Acids metabolism pharmacokinetics MeSH
- Mice, Inbred BALB C MeSH
- Nabumetone metabolism pharmacokinetics MeSH
- Specific Pathogen-Free Organisms MeSH
- Rats, Wistar MeSH
- Gastrointestinal Microbiome drug effects physiology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Video-Audio Media MeSH
- Journal Article MeSH
1. The underlying microbial metabolic activity toward xenobiotics is among the least explored factors contributing to the inter-individual variability in drug response. 2. Here, we analyzed the effect of microbiota on a non-steroidal anti-inflammatory drug nabumetone. 3. First, we cultivated the drug with the selected gut commensal and probiotic bacteria under both aerobic and anaerobic conditions and analyzed its metabolites by high-performance liquid chromatography (HPLC) with UV detection. To analyze the effect of microbiota on nabumetone pharmacokinetics in vivo, we administered a single oral dose of nabumetone to rodents with intentionally altered gut microbiome - either rats treated for three days with the antibiotic imipenem or to germ-free mice. Plasma levels of its main active metabolite 6 methoxy-2-naphthylacetic acid (6-MNA) were analyzed at pre-specified time intervals using HPLC with UV/fluorescence detection. 4. We found that nabumetone is metabolized by bacteria to its non-active metabolites and that this effect is stronger under anaerobic conditions. Although in vivo, none of the pharmacokinetic parameters of 6-MNA was significantly altered, there was a clear trend towards an increase of the AUC, Cmax and t1/2 in rats with reduced microbiota and germ-free mice.
e The Czech Academy of Sciences Institute of Microbiology Novy Hradek Czech Republic
The Czech Academy of Sciences Institute of Microbiology Novy Hradek Czech Republic
References provided by Crossref.org
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- $a 1. The underlying microbial metabolic activity toward xenobiotics is among the least explored factors contributing to the inter-individual variability in drug response. 2. Here, we analyzed the effect of microbiota on a non-steroidal anti-inflammatory drug nabumetone. 3. First, we cultivated the drug with the selected gut commensal and probiotic bacteria under both aerobic and anaerobic conditions and analyzed its metabolites by high-performance liquid chromatography (HPLC) with UV detection. To analyze the effect of microbiota on nabumetone pharmacokinetics in vivo, we administered a single oral dose of nabumetone to rodents with intentionally altered gut microbiome - either rats treated for three days with the antibiotic imipenem or to germ-free mice. Plasma levels of its main active metabolite 6 methoxy-2-naphthylacetic acid (6-MNA) were analyzed at pre-specified time intervals using HPLC with UV/fluorescence detection. 4. We found that nabumetone is metabolized by bacteria to its non-active metabolites and that this effect is stronger under anaerobic conditions. Although in vivo, none of the pharmacokinetic parameters of 6-MNA was significantly altered, there was a clear trend towards an increase of the AUC, Cmax and t1/2 in rats with reduced microbiota and germ-free mice.
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