Gut microbiota and host metabolizing enzymes co‐contribute to pharmacokinetic variability in type 2 diabetes mellitus rats

Abstract This study aimed to investigate the pharmacokinetic difference of quercetin between normal and type 2 diabetes mellitus (T2DM) rats. Our results showed that the mean residence time and half time were significantly increased, while the peak concentration was significantly reduced in T2DM rats, compared to the control rats. In addition, quercetin remained a high concentration in the liver for a long time with the highest concentration (13.51 ± 4.66 μg/mL) at 4 h after oral administration in T2DM rats. Furthermore, the CYP3A4 messenger RNA (mRNA) levels were downregulated and UGT1A1 mRNA levels in liver were upregulated in T2DM rats. In addition, the relative abundances of Bacteroides, norank, Parabacteroides , and Alistipes were decreased, while the relative abundances of Acrococcus, Frisingicoccus, Romboutsia , and Clostridium_sensu_stricto_1 were increased in the T2DM rats. The metabolism of quercetin in T2DM rats was slower compared to the normal group, which may be related to the lower level of CYP3A4 and the higher level of UGT1A1 in T2DM, as well as the significant enrichment of Acrococcus and other bacteria in the gut of T2DM rats.