Metformin has been shown to repress transcription of the bile salt export pump (BSEP) in human primary hepatocytes. The primary objective of this study was to assess the effect of oral metformin on the human pharmacokinetics (PK) of two BSEP probe substrates: pravastatin and chenodeoxycholic acid (CDCA). Endogenous bile acid levels were also assessed. An open-label, randomized, single-dose, placebo-controlled, fasted, crossover PK study was conducted in n=12 healthy adult volunteers. Metformin (500mg BID) or placebo was administered orally for 6 days. On day 7, a single dose of the BSEP substrates pravastatin and CDCA were administered orally. Plasma samples were quantified. Compared to placebo, metformin increased pravastatin plasma exposure, did not impact CDCA plasma exposure, and reduced conjugated primary bile acid levels in the blood. These results are consistent with metformin repressing BSEP expression. This differential effect reflects the degree of enterohepatic recirculation of victim substrates.
Learning Objectives:
Upon completion, participant will be able to list probe compounds for bile salt export pump (BSEP), including their different degrees of enterohepatic recirculation.
Upon completion, participant will be able to describe evidence supporting metformin to repress transcription of BSEP.
Upon completion, participant will be able to consider possible next steps to investigate BSEP repression
