Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11).

Article Details

Citation

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.

PubMed ID
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.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
AmiodaroneBile salt export pumpProteinHumans
No
Substrate
Inhibitor
Details
AstemizoleBile salt export pumpProteinHumans
No
Substrate
Details
AtazanavirBile salt export pumpProteinHumans
No
Substrate
Details
AtenololBile salt export pumpProteinHumans
No
Substrate
Details
AtorvastatinBile salt export pumpProteinHumans
No
Substrate
Details
AtropineBile salt export pumpProteinHumans
No
Substrate
Details
BenzbromaroneBile salt export pumpProteinHumans
No
Substrate
Details
BudesonideBile salt export pumpProteinHumans
No
Substrate
Details
CefaclorBile salt export pumpProteinHumans
No
Substrate
Details
CelecoxibBile salt export pumpProteinHumans
No
Inhibitor
Details
CerivastatinBile salt export pumpProteinHumans
No
Substrate
Details
ClarithromycinBile salt export pumpProteinHumans
No
Substrate
Details
ClotrimazoleBile salt export pumpProteinHumans
Unknown
Substrate
Inhibitor
Details
DiclofenacBile salt export pumpProteinHumans
No
Substrate
Details
DiethylstilbestrolBile salt export pumpProteinHumans
No
Substrate
Details
DihydroergocristineBile salt export pumpProteinHumans
No
Substrate
Details
DipyridamoleBile salt export pumpProteinHumans
No
Substrate
Details
DisulfiramBile salt export pumpProteinHumans
No
Substrate
Details
EfavirenzBile salt export pumpProteinHumans
No
Substrate
Details
ErythromycinBile salt export pumpProteinHumans
No
Substrate
Inhibitor
Details
EzetimibeBile salt export pumpProteinHumans
No
Substrate
Details
FelodipineBile salt export pumpProteinHumans
No
Substrate
Details
FenofibrateBile salt export pumpProteinHumans
No
Substrate
Details
FlucloxacillinBile salt export pumpProteinHumans
No
Substrate
Details
FluvoxamineBile salt export pumpProteinHumans
No
Substrate
Details
GlimepirideBile salt export pumpProteinHumans
No
Substrate
Details
GlipizideBile salt export pumpProteinHumans
No
Substrate
Details
GlyburideBile salt export pumpProteinHumans
Unknown
Substrate
Inhibitor
Details
Glycyrrhizic acidBile salt export pumpProteinHumans
No
Substrate
Details
ImatinibBile salt export pumpProteinHumans
No
Substrate
Details
IndinavirBile salt export pumpProteinHumans
No
Substrate
Details
Indocyanine green acid formBile salt export pumpProteinHumans
No
Substrate
Details
IndomethacinBile salt export pumpProteinHumans
No
Substrate
Details
IsradipineBile salt export pumpProteinHumans
No
Substrate
Details
KetoconazoleBile salt export pumpProteinHumans
Unknown
Inhibitor
Details
LopinavirBile salt export pumpProteinHumans
No
Inhibitor
Details
LoratadineBile salt export pumpProteinHumans
Unknown
Substrate
Details
LosartanBile salt export pumpProteinHumans
No
Substrate
Details
LovastatinBile salt export pumpProteinHumans
No
Substrate
Details
MifepristoneBile salt export pumpProteinHumans
No
Substrate
Details
NaproxenBile salt export pumpProteinHumans
No
Substrate
Details
NefazodoneBile salt export pumpProteinHumans
No
Substrate
Details
NelfinavirBile salt export pumpProteinHumans
No
Substrate
Details
NicardipineBile salt export pumpProteinHumans
No
Substrate
Details
NifedipineBile salt export pumpProteinHumans
No
Inhibitor
Details
NitrendipineBile salt export pumpProteinHumans
No
Substrate
Details
NitrofurantoinBile salt export pumpProteinHumans
No
Substrate
Details
OfloxacinBile salt export pumpProteinHumans
No
Substrate
Details
OlmesartanBile salt export pumpProteinHumans
No
Inhibitor
Details
PilsicainideBile salt export pumpProteinHumans
No
Substrate
Details
PitavastatinBile salt export pumpProteinHumans
No
Substrate
Details
Prasterone sulfateBile salt export pumpProteinHumans
No
Substrate
Details
RanolazineBile salt export pumpProteinHumans
No
Substrate
Details
RepaglinideBile salt export pumpProteinHumans
No
Substrate
Details
RitonavirBile salt export pumpProteinHumans
No
Inhibitor
Details
RosiglitazoneBile salt export pumpProteinHumans
No
Substrate
Details
SaquinavirBile salt export pumpProteinHumans
No
Substrate
Details
SimvastatinBile salt export pumpProteinHumans
No
Substrate
Details
SpironolactoneBile salt export pumpProteinHumans
No
Substrate
Details
SulfamethoxazoleBile salt export pumpProteinHumans
No
Inhibitor
Details
SulfinpyrazoneBile salt export pumpProteinHumans
No
Substrate
Details
TelmisartanBile salt export pumpProteinHumans
No
Substrate
Details
TerfenadineBile salt export pumpProteinHumans
No
Substrate
Details
TinidazoleBile salt export pumpProteinHumans
No
Substrate
Details
TipranavirBile salt export pumpProteinHumans
Unknown
Substrate
Inhibitor
Details
Drug Interactions
DrugsInteraction
Bosentan
Reserpine
The risk or severity of liver damage can be increased when Reserpine is combined with Bosentan.
Bosentan
Cimetidine
The risk or severity of liver damage can be increased when Cimetidine is combined with Bosentan.
Bosentan
Olmesartan
The risk or severity of liver damage can be increased when Olmesartan is combined with Bosentan.
Chlorpromazine
Olmesartan
The risk or severity of liver damage can be increased when Olmesartan is combined with Chlorpromazine.
Cimetidine
Troglitazone
The risk or severity of liver damage can be increased when Troglitazone is combined with Cimetidine.
Cimetidine
Olmesartan
The risk or severity of liver damage can be increased when Olmesartan is combined with Cimetidine.
Ethinylestradiol
Reserpine
The risk or severity of liver damage can be increased when Reserpine is combined with Ethinylestradiol.
Ethinylestradiol
Progesterone
The risk or severity of liver damage can be increased when Progesterone is combined with Ethinylestradiol.
Ethinylestradiol
Chlorpromazine
The risk or severity of liver damage can be increased when Chlorpromazine is combined with Ethinylestradiol.
Ethinylestradiol
Cimetidine
The risk or severity of liver damage can be increased when Cimetidine is combined with Ethinylestradiol.
Interactions
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