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Antibiotic-induced depletion of gut microbiota increases systemic exposure of clopidogrel active metabolite in type 2 diabetic rats
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  • Xue Chen,
  • Yingrui Liu,
  • Hongwei Yao,
  • Wenfang Song,
  • Meng Pan,
  • Yu Song,
  • Jingkai Gu,
  • Yingjie Guo
Xue Chen
Jilin University
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Yingrui Liu
Jilin University
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Hongwei Yao
Jilin University
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Wenfang Song
Jilin University
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Meng Pan
Jilin University
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Yu Song
Hainan Tropical Ocean University
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Jingkai Gu
Jilin University
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Yingjie Guo
Jilin University
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Abstract

Background and Purpose: The current study investigated whether the manipulation of gut microbiome through treatment with an antibiotic cocktail can alter the bioavailability of clopidogrel active metabolite (Clop-AM) in T2DM rats. Experimental Approach: Control and T2DM rats were orally administered with either vehicle or an antibiotic cocktail containing ampicillin, neomycin, metronidazole, and vancomycin for 5 consecutive days. The levels of clopidogrel (Clop) and its metabolites were measured by LC-MS/MS. Biochemical parameters, liver microsome metabolism, mRNA, protein or activity of Clop- metabolizing enzymes and transporter, and 16S rRNA sequence of fecal samples were analyzed to explain any altered pharmacokinetic profile of Clop-AM. Key Results: Antibiotic administration markedly alleviated T2DM rats’ phenotypes including hyperglycemia, hyperlipidemia, insulin resistance, liver dysfunction and inflammation. Meanwhile, the reduced systemic exposure of Clop-AM in T2DM rats as compared to control rats was significantly reversed after antibiotic treatment, accompanied with the decreased expression of P-glycoprotein (P-gp) in small intestine, suggesting P-gp-based Clop absorption might be promoted, consequently making more Clop available for Clop-AM formation. Interestingly, fecal microbiome analysis exhibited the reduced microbial amount and the altered microbial composition in antibiotic-treated T2DM rats. Especially, there was an inconsistent change of P-gp levels between T2DM rats and SW480 cells after antibiotic treatment, suggesting antibiotic-induced microbiome depletion, not the direct role of antibiotics is associated with the enhanced Clop-AM plasma exposure in T2DM rats. Conclusion and Implication: The findings show that gut microbiota modulation is an effective therapeutic strategy to enhance Clop-AM generation under T2DM conditions.

Peer review status:UNDER REVIEW

12 Nov 2021Submitted to British Journal of Pharmacology
18 Nov 2021Assigned to Editor
18 Nov 2021Submission Checks Completed
26 Nov 2021Reviewer(s) Assigned
17 Jan 2022Review(s) Completed, Editorial Evaluation Pending