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Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes.
PLoS One. 2014; 9(1):e87548.Plos

Abstract

BACKGROUND

Inhibition of the transporter-mediated hepatobiliary elimination of bile salts is a putative mechanism for liver toxicity observed with some endothelin receptor antagonists (ERAs).

METHODS

Sandwich-cultured human hepatocytes were used to study the hepatobiliary distribution and accumulation of exogenous taurocholate, ERAs and endogenous bile acids. The molecular mechanisms for findings in hepatocytes or clinical observations were further explored using either vesicular assays (efflux transporters) or transfected cell-lines (uptake transporters). Inhibition constants (IC50) were measured for the human hepatobiliary transporters bile salt export pump (BSEP), sodium taurocholate cotransporting polypeptide (NTCP), multidrug resistance protein 2 (MRP2), P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3.

RESULTS

The ERAs showed dose-dependent reductions in exogenous taurocholate cellular accumulation in human hepatocytes, with macitentan having the greatest effect. Consistent with their effects on bile acids, the ERAs inhibited bile transporters. IC50 values for OATP1B1 and OATP1B3 ranged from 2 µM for macitentan to 47 µM for ambrisentan. Macitentan and bosentan also inhibited NTCP with IC50 values of 10 and 36 µM, respectively. Similar to previously reported findings with sitaxsentan, BSEP inhibition was observed for bosentan and macitentan with IC50 values of 42 and 12 µM, respectively. In contrast, ambrisentan showed little or no inhibition of these transporters. Other transporters tested were weakly inhibited by the ERAs. Accumulation in hepatocytes was also a factor in the effects on bile transport. Macitentan demonstrated the greatest accumulation in human hepatocytes (∼100x) followed by sitaxsentan (∼40x), bosentan (∼20x) and ambrisentan (∼2x).

CONCLUSIONS

Significant differences in the inhibition of hepatic transporters were observed between the evaluated ERAs in vitro. Macitentan had the highest level of cellular accumulation and caused the greatest effects on bile acid distribution in human hepatocytes followed by sitaxsentan and bosentan. Ambrisentan showed a low potential to affect bile acids.

Authors+Show Affiliations

Gilead Sciences, Inc., Foster City, California, United States of America.Gilead Sciences, Inc., Foster City, California, United States of America.Qualyst Transporter Solutions, LLC, Durham, North Carolina, United States of America.Gilead Sciences, Inc., Foster City, California, United States of America.Qualyst Transporter Solutions, LLC, Durham, North Carolina, United States of America.Qualyst Transporter Solutions, LLC, Durham, North Carolina, United States of America.Qualyst Transporter Solutions, LLC, Durham, North Carolina, United States of America.Gilead Sciences, Inc., Foster City, California, United States of America.

Pub Type(s)

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

Language

eng

PubMed ID

24498134

Citation

Lepist, Eve-Irene, et al. "Evaluation of the Endothelin Receptor Antagonists Ambrisentan, Bosentan, Macitentan, and Sitaxsentan as Hepatobiliary Transporter Inhibitors and Substrates in Sandwich-cultured Human Hepatocytes." PloS One, vol. 9, no. 1, 2014, pp. e87548.
Lepist EI, Gillies H, Smith W, et al. Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes. PLoS One. 2014;9(1):e87548.
Lepist, E. I., Gillies, H., Smith, W., Hao, J., Hubert, C., St Claire, R. L., Brouwer, K. R., & Ray, A. S. (2014). Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes. PloS One, 9(1), e87548. https://doi.org/10.1371/journal.pone.0087548
Lepist EI, et al. Evaluation of the Endothelin Receptor Antagonists Ambrisentan, Bosentan, Macitentan, and Sitaxsentan as Hepatobiliary Transporter Inhibitors and Substrates in Sandwich-cultured Human Hepatocytes. PLoS One. 2014;9(1):e87548. PubMed PMID: 24498134.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes. AU - Lepist,Eve-Irene, AU - Gillies,Hunter, AU - Smith,William, AU - Hao,Jia, AU - Hubert,Cassandra, AU - St Claire,Robert L,3rd AU - Brouwer,Kenneth R, AU - Ray,Adrian S, Y1 - 2014/01/30/ PY - 2013/09/16/received PY - 2013/12/30/accepted PY - 2014/2/6/entrez PY - 2014/2/6/pubmed PY - 2014/9/10/medline SP - e87548 EP - e87548 JF - PloS one JO - PLoS One VL - 9 IS - 1 N2 - BACKGROUND: Inhibition of the transporter-mediated hepatobiliary elimination of bile salts is a putative mechanism for liver toxicity observed with some endothelin receptor antagonists (ERAs). METHODS: Sandwich-cultured human hepatocytes were used to study the hepatobiliary distribution and accumulation of exogenous taurocholate, ERAs and endogenous bile acids. The molecular mechanisms for findings in hepatocytes or clinical observations were further explored using either vesicular assays (efflux transporters) or transfected cell-lines (uptake transporters). Inhibition constants (IC50) were measured for the human hepatobiliary transporters bile salt export pump (BSEP), sodium taurocholate cotransporting polypeptide (NTCP), multidrug resistance protein 2 (MRP2), P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. RESULTS: The ERAs showed dose-dependent reductions in exogenous taurocholate cellular accumulation in human hepatocytes, with macitentan having the greatest effect. Consistent with their effects on bile acids, the ERAs inhibited bile transporters. IC50 values for OATP1B1 and OATP1B3 ranged from 2 µM for macitentan to 47 µM for ambrisentan. Macitentan and bosentan also inhibited NTCP with IC50 values of 10 and 36 µM, respectively. Similar to previously reported findings with sitaxsentan, BSEP inhibition was observed for bosentan and macitentan with IC50 values of 42 and 12 µM, respectively. In contrast, ambrisentan showed little or no inhibition of these transporters. Other transporters tested were weakly inhibited by the ERAs. Accumulation in hepatocytes was also a factor in the effects on bile transport. Macitentan demonstrated the greatest accumulation in human hepatocytes (∼100x) followed by sitaxsentan (∼40x), bosentan (∼20x) and ambrisentan (∼2x). CONCLUSIONS: Significant differences in the inhibition of hepatic transporters were observed between the evaluated ERAs in vitro. Macitentan had the highest level of cellular accumulation and caused the greatest effects on bile acid distribution in human hepatocytes followed by sitaxsentan and bosentan. Ambrisentan showed a low potential to affect bile acids. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24498134/Evaluation_of_the_endothelin_receptor_antagonists_ambrisentan_bosentan_macitentan_and_sitaxsentan_as_hepatobiliary_transporter_inhibitors_and_substrates_in_sandwich_cultured_human_hepatocytes_ L2 - https://dx.plos.org/10.1371/journal.pone.0087548 DB - PRIME DP - Unbound Medicine ER -