Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11).
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Pedersen JM, Matsson P, Bergstrom CA, Hoogstraate J, Noren A, LeCluyse EL, Artursson P
Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11).
Toxicol Sci. 2013 Dec;136(2):328-43. doi: 10.1093/toxsci/kft197. Epub 2013 Sep 6.
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- 24014644 [ View in PubMed]
- Abstract
A comprehensive analysis was performed to investigate how inhibition of the human bile salt export pump (BSEP/ABCB11) relates to clinically observed drug-induced liver injury (DILI). Inhibition of taurocholate (TA) transport was investigated in BSEP membrane vesicles for a data set of 250 compounds, and 86 BSEP inhibitors were identified. Structure-activity modeling identified BSEP inhibition to correlate strongly with compound lipophilicity, whereas positive molecular charge was associated with a lack of inhibition. All approved drugs in the data set (n = 182) were categorized according to DILI warnings in drug labels issued by the Food and Drug Administration, and a strong correlation between BSEP inhibition and DILI was identified. As many as 38 of the 61 identified BSEP inhibitors were associated with severe DILI, including 9 drugs not previously linked to BSEP inhibition. Further, among the tested compounds, every second drug associated with severe DILI was a BSEP inhibitor. Finally, sandwich-cultured human hepatocytes (SCHH) were used to investigate the relationship between BSEP inhibition, TA transport, and clinically observed DILI in detail. BSEP inhibitors associated with severe DILI greatly reduced the TA canalicular efflux, whereas BSEP inhibitors with less severe or no DILI resulted in weak or no reduction of TA efflux in SCHH. This distinction illustrates the usefulness of SCHH in refined analysis of BSEP inhibition. In conclusion, BSEP inhibition in membrane vesicles was found to correlate to DILI severity, and altered disposition of TA in SCHH was shown to separate BSEP inhibitors associated with severe DILI from those with no or mild DILI.
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Drugs Interaction Integrate drug-drug
interactions in your softwareBosentanReserpine The risk or severity of liver damage can be increased when Reserpine is combined with Bosentan. BosentanCimetidine The risk or severity of liver damage can be increased when Cimetidine is combined with Bosentan. BosentanOlmesartan The risk or severity of liver damage can be increased when Olmesartan is combined with Bosentan. ChlorpromazineOlmesartan The risk or severity of liver damage can be increased when Olmesartan is combined with Chlorpromazine. CimetidineTroglitazone The risk or severity of liver damage can be increased when Troglitazone is combined with Cimetidine.