In vivo pharmacodynamic and pharmacokinetic effects of metformin mediated by the gut microbiota in rats.

Aims: The gut microbiota plays a crucial role in the efficacy of metformin in T2DM treatment. We evaluated whether the pharmacodynamics and pharmacokinetics of metformin are mediated by gut microbiota.

Main Methods: We used conventional diabetic and pseudo-germ-free rats. After 6 weeks of metformin treatment, pharmacodynamic indexes were determined. Metformin concentrations were measured with a validated HPLC-MS/MS method after the first oral administration.

Key Findings: Most endpoints were similar between vehicle-treated diabetic and vehicle-treated pseudo-germ-free diabetic rats. However, after 6 weeks of metformin treatment, compared with conventional diabetic rats, pseudo-germ-free diabetic rats exhibited significantly increased FBG, decreased oral glucose, reduced GSP, worsened insulin resistance, increased hyperlipidemia, and increased hepatic steatosis severity. Moreover, the Cmax of pseudo-germ-free rats increased significantly, while the t1/2α decreased significantly. These pharmacodynamic and pharmacokinetic changes were probably due to a decrease in Oct1 expression in the liver, resulting in altered hepatic uptake of metformin in vivo.

Significance: These results implied that the gut microbiota may play an important role in the pharmacodynamics and pharmacokinetics of metformin and that the changes in these properties are probably due to Oct1 downregulation in the livers of pseudo-germ-free rats.