Differential effects of metformin-mediated BSEP repression on pravastatin and bile acid pharmacokinetics in humans: A randomized controlled trial.

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 (PKs) of two BSEP probe substrates: pravastatin and chenodeoxycholic acid (CDCA; also known as chenodiol). Endogenous bile acid levels were assessed as a secondary measure of metformin impact. An open-label, randomized, single-dose, placebo-controlled, fasted, crossover PK study was conducted in 12 healthy adult volunteers. Metformin (500 mg b.i.d.) or placebo (b.i.d.) was administered orally for 6 days. On day 7, a single dose of the BSEP substrates pravastatin (80 mg) and CDCA (250 mg) were administered orally. Plasma samples were quantified for pravastatin, CDCA, and endogenous bile acids. 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.