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Early Identification of Clinically Relevant Drug Interactions with the Human Bile Salt Export Pump (BSEP; ABCB11)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Drug Delivery)ORCID iD: 0000-0002-9701-4489
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Drug Delivery)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Drug Delivery)
Acturum Life Science AB, Södertälje, Sweden.
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2013 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 136, no 2, 328-343 p.Article in journal (Other academic) Published
Abstract [en]

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. 

Place, publisher, year, edition, pages
2013. Vol. 136, no 2, 328-343 p.
Keyword [en]
Bile Salt Export Pump, ABCB11, BSEP, ABC transporters, drug transport, inhibition, structure-activity relationships, transport proteins, Drug Induced Liver Injury, DILI
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-204168DOI: 10.1093/toxsci/kft197ISI: 000328695500006OAI: diva2:637847
Available from: 2013-07-23 Created: 2013-07-23 Last updated: 2015-02-19Bibliographically approved
In thesis
1. ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury
Open this publication in new window or tab >>ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Membrane transport proteins are known to influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. At the onset of this thesis work, only a few structure-activity models, in general describing P-glycoprotein (Pgp/ABCB1) interactions, were developed using small datasets with little structural diversity. In this thesis, drug-transport protein interactions were explored using large, diverse datasets representing the chemical space of orally administered registered drugs. Focus was set on the ATP-binding cassette (ABC) transport proteins expressed in the canalicular membrane of human hepatocytes.

The inhibition of the ABC transport proteins multidrug-resistance associated protein 2 (MRP2/ABCC2) and bile salt export pump (BSEP/ABCB11) was experimentally investigated using membrane vesicles from cells overexpressing the investigated proteins and sandwich cultured human hepatocytes (SCHH). Several previously unknown inhibitors were identified for both of the proteins and predictive in silico models were developed. Furthermore, a clear association between BSEP inhibition and clinically reported drug induced liver injuries (DILI) was identified. For the first time, an in silico model that described combined inhibition of Pgp, MRP2 and breast cancer resistance protein (BCRP/ABCG2) was developed using a large, structurally diverse dataset. Lipophilic weak bases were more often found to be general ABC inhibitors in comparison to other drugs. In early drug discovery, in silico models can be used as predictive filters in the drug candidate selection process and membrane vesicles as a first experimental screening tool to investigate protein interactions.

In summary, the present work has led to an increased understanding of molecular properties important in ABC inhibition as well as the potential influence of ABC proteins in adverse drug reactions. A number of previously unknown ABC inhibitors were identified and predictive computational models were developed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 67 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 172
ABC transport protein, Pgp, P-glycoprotein, ABCB1, BCRP, breast cancer resistance protein, ABCG2, MRP2, multidrug resistance-associated protein 2, ABCC2, BSEP, bile salt export pump, ABCB11, sandwich cultured human hepatocytes, SCHH, drug-induced liver injury, DILI, multivariate data analysis, OPLS
National Category
Pharmaceutical Sciences
Research subject
urn:nbn:se:uu:diva-205355 (URN)978-91-554-8702-7 (ISBN)
Public defence
2013-09-06, B21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Available from: 2013-08-16 Created: 2013-08-16 Last updated: 2014-04-16

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