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

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    Author
    Metry, Melissa
    Krug, Samuel A
    Karra, Vijaya Kumari
    Kane, Maureen A
    Fink, Jeffrey C
    Shu, Yan
    Wang, Hongbing
    Polli, James E
    Date
    2022-07-28
    Journal
    Clinical and Translational Science
    Publisher
    Wiley-Blackwell
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1111/cts.13375
    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. © 2022 The Authors.
    Rights/Terms
    © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/19572
    ae974a485f413a2113503eed53cd6c53
    10.1111/cts.13375
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