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Early Identificatio...
Early Identification of Clinically Relevant Drug Interactions with the Human Bile Salt Export Pump (BSEP; ABCB11)
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- Pedersen, Jenny M., 1979- (författare)
- Uppsala universitet,Institutionen för farmaci,Drug Delivery
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- Matsson, Pär (författare)
- Uppsala universitet,Institutionen för farmaci,Drug Delivery
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- Bergström, Christel A. S. (författare)
- Uppsala universitet,Institutionen för farmaci,Drug Delivery
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- Hoogstraate, Janet (författare)
- Acturum Life Science AB, Södertälje, Sweden
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- Norén, Agneta (författare)
- Uppsala universitet,Gastrointestinalkirurgi
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- LeCluyse, Edward L. (författare)
- The Hamner Institutes for Health Sciences, North Carolina, USA
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- Artursson, Per (författare)
- Uppsala universitet,Institutionen för farmaci,Drug Delivery
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(creator_code:org_t)
- 2013-09-06
- 2013
- Engelska.
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Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 136:2, s. 328-343
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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 dataset of 250 compounds, and 86 BSEP inhibitors were identified. Structure-activity modeling identified BSEP inhibition to correlate strongly with compound lipophilicity, while positive molecular charge was associated with a lack of inhibition. All approved drugs in the dataset (n=182) were categorized according to DILI warnings in drug labels issued by the FDA 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 nine 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 while 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- Bile Salt Export Pump
- ABCB11
- BSEP
- ABC transporters
- drug transport
- inhibition
- structure-activity relationships
- transport proteins
- Drug Induced Liver Injury
- DILI
Publikations- och innehållstyp
- vet (ämneskategori)
- art (ämneskategori)
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