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Research ArticleToxicology

Bosentan Alters Endo- and Exogenous Bile Salt Disposition in Sandwich-Cultured Human Hepatocytes

Marlies Oorts, Pieter Van Brantegem, Neel Deferm, Sagnik Chatterjee, Erwin Dreesen, Axelle Cooreman, Mathieu Vinken, Lysiane Richert and Pieter Annaert
Journal of Pharmacology and Experimental Therapeutics October 2021, 379 (1) 20-32; DOI: https://doi.org/10.1124/jpet.121.000695
Marlies Oorts
Drug Delivery and Disposition (M.O., P.V.B., N.D., P.A.) and Clinical Pharmacology and Pharmacotherapy (E.D.), Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (A.C.); Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center, Syngene International, Bangalore, India (S.C.); Uppsala Pharmacometrics Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden (E.D.); Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium (M.V.); KaLy-Cell, Plobsheim, France (L.R.); and BioNotus, Niel, Belgium (P.A.)
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Pieter Van Brantegem
Drug Delivery and Disposition (M.O., P.V.B., N.D., P.A.) and Clinical Pharmacology and Pharmacotherapy (E.D.), Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (A.C.); Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center, Syngene International, Bangalore, India (S.C.); Uppsala Pharmacometrics Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden (E.D.); Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium (M.V.); KaLy-Cell, Plobsheim, France (L.R.); and BioNotus, Niel, Belgium (P.A.)
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Neel Deferm
Drug Delivery and Disposition (M.O., P.V.B., N.D., P.A.) and Clinical Pharmacology and Pharmacotherapy (E.D.), Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (A.C.); Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center, Syngene International, Bangalore, India (S.C.); Uppsala Pharmacometrics Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden (E.D.); Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium (M.V.); KaLy-Cell, Plobsheim, France (L.R.); and BioNotus, Niel, Belgium (P.A.)
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Sagnik Chatterjee
Drug Delivery and Disposition (M.O., P.V.B., N.D., P.A.) and Clinical Pharmacology and Pharmacotherapy (E.D.), Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (A.C.); Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center, Syngene International, Bangalore, India (S.C.); Uppsala Pharmacometrics Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden (E.D.); Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium (M.V.); KaLy-Cell, Plobsheim, France (L.R.); and BioNotus, Niel, Belgium (P.A.)
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Erwin Dreesen
Drug Delivery and Disposition (M.O., P.V.B., N.D., P.A.) and Clinical Pharmacology and Pharmacotherapy (E.D.), Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (A.C.); Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center, Syngene International, Bangalore, India (S.C.); Uppsala Pharmacometrics Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden (E.D.); Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium (M.V.); KaLy-Cell, Plobsheim, France (L.R.); and BioNotus, Niel, Belgium (P.A.)
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Axelle Cooreman
Drug Delivery and Disposition (M.O., P.V.B., N.D., P.A.) and Clinical Pharmacology and Pharmacotherapy (E.D.), Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (A.C.); Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center, Syngene International, Bangalore, India (S.C.); Uppsala Pharmacometrics Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden (E.D.); Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium (M.V.); KaLy-Cell, Plobsheim, France (L.R.); and BioNotus, Niel, Belgium (P.A.)
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Mathieu Vinken
Drug Delivery and Disposition (M.O., P.V.B., N.D., P.A.) and Clinical Pharmacology and Pharmacotherapy (E.D.), Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (A.C.); Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center, Syngene International, Bangalore, India (S.C.); Uppsala Pharmacometrics Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden (E.D.); Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium (M.V.); KaLy-Cell, Plobsheim, France (L.R.); and BioNotus, Niel, Belgium (P.A.)
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Lysiane Richert
Drug Delivery and Disposition (M.O., P.V.B., N.D., P.A.) and Clinical Pharmacology and Pharmacotherapy (E.D.), Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (A.C.); Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center, Syngene International, Bangalore, India (S.C.); Uppsala Pharmacometrics Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden (E.D.); Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium (M.V.); KaLy-Cell, Plobsheim, France (L.R.); and BioNotus, Niel, Belgium (P.A.)
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Pieter Annaert
Drug Delivery and Disposition (M.O., P.V.B., N.D., P.A.) and Clinical Pharmacology and Pharmacotherapy (E.D.), Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (A.C.); Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center, Syngene International, Bangalore, India (S.C.); Uppsala Pharmacometrics Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden (E.D.); Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium (M.V.); KaLy-Cell, Plobsheim, France (L.R.); and BioNotus, Niel, Belgium (P.A.)
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Abstract

Bosentan, a well–known cholestatic agent, was not identified as cholestatic at concentrations up to 200 µM based on the drug-induced cholestasis (DIC) index value, determined in a sandwich-cultured human hepatocyte (SCHH)–based DIC assay. To obtain further quantitative insights into the effects of bosentan on cellular bile salt handling by human hepatocytes, the present study determined the effect of 2.5–25 µM bosentan on endogenous bile salt levels and on the disposition of 10 µM chenodeoxycholic acid (CDCA) added to the medium in SCHHs. Bosentan reduced intracellular as well as extracellular concentrations of both endogenous glycochenodeoxycholic acid (GCDCA) and glycocholic acid in a concentration-dependent manner. When exposed to 10 µM CDCA, bosentan caused a shift from canalicular efflux to sinusoidal efflux of GCDCA. CDCA levels were not affected. Our mechanistic model confirmed the inhibitory effect of bosentan on canalicular GCDCA clearance. Moreover, our results in SCHHs also indicated reduced GCDCA formation. We confirmed the direct inhibitory effect of bosentan on CDCA conjugation with glycine in incubations with liver S9 fraction.

SIGNIFICANCE STATEMENT Bosentan was evaluated at therapeutically relevant concentrations (2.5–25 µM) in sandwich-cultured human hepatocytes. It altered bile salt disposition and inhibited canalicular secretion of glycochenodeoxycholic acid (GCDCA). Within 24 hours, bosentan caused a shift from canalicular to sinusoidal efflux of GCDCA. These results also indicated reduced GCDCA formation. This study confirmed a direct effect of bosentan on chenodeoxycholic acid conjugation with glycine in liver S9 fraction.

Footnotes

    • Received April 25, 2021.
    • Accepted July 28, 2021.
  • ↵1 M.O. and P.V.B. contributed equally to this work as first authors.

  • This research was supported by a research grant of the Research Foundation Flanders [Grant G012318N]. E.D. is a postdoctoral research fellow of the Research Foundation Flanders (FWO), Belgium [Grant 12X9420N].

  • https://dx.doi.org/10.1124/jpet.121.000695.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 379 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 379, Issue 1
1 Oct 2021
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Research ArticleToxicology

Bosentan Alters Bile Salt Disposition

Marlies Oorts, Pieter Van Brantegem, Neel Deferm, Sagnik Chatterjee, Erwin Dreesen, Axelle Cooreman, Mathieu Vinken, Lysiane Richert and Pieter Annaert
Journal of Pharmacology and Experimental Therapeutics October 1, 2021, 379 (1) 20-32; DOI: https://doi.org/10.1124/jpet.121.000695

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Research ArticleToxicology

Bosentan Alters Bile Salt Disposition

Marlies Oorts, Pieter Van Brantegem, Neel Deferm, Sagnik Chatterjee, Erwin Dreesen, Axelle Cooreman, Mathieu Vinken, Lysiane Richert and Pieter Annaert
Journal of Pharmacology and Experimental Therapeutics October 1, 2021, 379 (1) 20-32; DOI: https://doi.org/10.1124/jpet.121.000695
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