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

Abstract

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.

Finasteride delays atherosclerosis progression in mice and is associated with a reduction in plasma cholesterol in men

“…Bile acid measurements were performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as previously described ( 27 , 28 , 29 ). Briefly, 100 μl of plasma were loaded directly onto the ISOLUTE PLD+ column per manufacturer’s instructions, and 5 μl of internal standard (1 μg/ml deuterated bile acids stock) was added to each tube.…”

“…Homogenate was centrifuged at 4000 rpm for 5 min, and 600 μl of supernatant was combined with 30 μl of internal standard and 3 ml of 5% ammonium hydroxide to precipitate proteins. Samples were then allowed to shake at room temperature for 2 h and the organic layer was then passed through the PLD+ column and reconstituted as listed above ( 27 , 28 , 29 ).…”

Research progress on the relationship between bile acid metabolism and type 2 diabetes mellitus

“…However, it's worth noting that these studies do not measure changes of BA concentrations. In addition, many studies have reported that metformin can inhibit the expression of the bile acid transporter BESP by activating cAMP-PKA and cAMP-AMPK pathways, although it does not appear to affect the expression of CYP7A1 [38][39][40]. This implies that metformin may influence not only bile acid synthesis, but also bile acid secretion and reuptake.…”