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

Antihypertensive Agents / metabolism Bile Acids and Salts / metabolism Bosentan / metabolism Cells, Cultured Culture Media / metabolism Dose-Response Relationship, Drug Extracellular Fluid / drug effects Hepatocytes / drug effects Humans

Journal

The Journal of pharmacology and experimental therapeutics
ISSN: 1521-0103
Titre abrégé: J Pharmacol Exp Ther
Pays: United States
ID NLM: 0376362

Informations de publication

Date de publication:
10 2021
Historique:
received: 25 04 2021
accepted: 28 07 2021
pubmed: 6 8 2021
medline: 31 12 2021
entrez: 5 8 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1124/jpet.121.000695 PMID: 34349015
pubmed: 34349015
pii: jpet.121.000695
doi: 10.1124/jpet.121.000695
doi:

Substances chimiques

Antihypertensive Agents 0
Bile Acids and Salts 0
Culture Media 0
Bosentan Q326023R30

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

20-32

Informations de copyright

Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.

Auteurs

Marlies Oorts (M)

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.).

Pieter Van Brantegem (P)

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.).

Neel Deferm (N)

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.).

Sagnik Chatterjee (S)

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.).

Erwin Dreesen (E)

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.).

Axelle Cooreman (A)

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.).

Mathieu Vinken (M)

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.).

Lysiane Richert (L)

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.).

Pieter Annaert (P)

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.) Pieter.annaert@kuleuven.be.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents cardiovasculaires › Antihypertenseurs › Bosentan Alters Endo- and Exogenous Bile Salt...
questionsmedicales.fr › Composés polycycliques › Composés à cycles fusionnés › Stéroïdes › Acides et sels biliaires › Bosentan Alters Endo- and Exogenous Bile Salt...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Bosentan › Bosentan Alters Endo- and Exogenous Bile Salt...
questionsmedicales.fr › Cellules › Cellules cultivées › Bosentan Alters Endo- and Exogenous Bile Salt...
questionsmedicales.fr › Équipement et fournitures › Milieux de culture › Bosentan Alters Endo- and Exogenous Bile Salt...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › Bosentan Alters Endo- and Exogenous Bile Salt...
questionsmedicales.fr › Liquides et sécrétions biologiques › Liquides biologiques › Liquide extracellulaire › Bosentan Alters Endo- and Exogenous Bile Salt...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › Bosentan Alters Endo- and Exogenous Bile Salt...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Bosentan Alters Endo- and Exogenous Bile Salt...