TY - JOUR T1 - Antibiotics-Induced Disruption of Gut Microbiota Increases Systemic Exposure of Clopidogrel Active Metabolite in Type 2 Diabetic Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1142 LP - 1150 DO - 10.1124/dmd.122.000906 VL - 50 IS - 9 AU - Xue Chen AU - Yingrui Liu AU - Hongwei Yao AU - Wenfang Song AU - Yu Song AU - Jingkai Gu AU - Yingjie Guo Y1 - 2022/09/01 UR - http://dmd.aspetjournals.org/content/50/9/1142.abstract N2 - Gut microbiota play an important role in the pathophysiology of type 2 diabetic mellitus (T2DM) and biodisposition of drugs. Our previous study demonstrated that T2DM rats had the decreased plasma exposure of clopidogrel active metabolite (Clop-AM) due to upregulation of P-glycoprotein (P-gp). However, whether the change to clopidogrel (Clop) disposition under T2DM conditions is associated with gut microbiota needs to be elucidated. In the study, we used an antibiotic cocktail consisting of ampicillin, vancomycin, metronidazole, and neomycin to disrupt gut microbiota and observed its influence on pharmacokinetic profiles of Clop-AM. Antibiotic administration markedly alleviated T2DM rats’ phenotype, including hyperglycemia, insulin resistance, oxidative stress, inflammation, hyperlipidemia, and liver dysfunction. Meanwhile, treatment with antibiotics significantly reversed the reduced systemic exposure of Clop-AM in T2DM rats relative to control rats, which was associated with the decreased intestinal P-gp level that might promote Clop absorption, resulting in more Clop transformation to Clop-AM. Fecal microbiome analysis exhibited a serious disruption of gut microbiota after antibiotic treatment with the sharply reduced microbial load and the altered microbial composition. Interestingly, an in vitro study showed that antibiotics had no influence on P-gp mRNA levels in SW480 cells, suggesting that the microbiome disruption, not the direct role of antibiotics on P-gp expression, contributes to the altered P-gp level and Clop disposition in T2DM rats. The findings add new insights into the potential impact of gut microbiota on Clop biodisposition.SIGNIFICANCE STATEMENT Antibiotics increase systemic exposure of Clop-AM in T2DM rats, which is associated with the downregulation of P-gp levels. Antibiotics-induced disruption of gut microbiota, not the direct effect of antibiotics on P-gp and cytochrome P450 expression, contributes to the altered Clop disposition. Antibiotics also alleviate the T2DM phenotype, including hyperglycemia, hyperlipidemia, insulin resistance, liver dysfunction, and inflammation. ER -