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.