Early Identification of Clinically Relevant Drug Interactions With the Human Bile Salt Export Pump (BSEP/ABCB11)

Pedersen, Jenny M.; Matsson, Pär; Bergström, Christel A S; Hoogstraate, Janet; Norén, Agneta; LeCluyse, Edward L.; Artursson, Per

doi:10.1093/toxsci/kft197

Cited by 136 publications

(167 citation statements)

References 39 publications

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“…2012; Pedersen et al. 2013). Thus, these investigations suggest that cyclosporin‐induced impairment of bile acid efflux and cholestasis could be secondary to ER stress only for high concentrations of this immunosuppressant.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

188

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

188

161

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“…Their best model reached an accuracy of 0.87 (on a test set of 187 compounds). Finally, Pedersen and colleagues 10 built two orthogonal partial least-squares discriminant analysis (OPLS-DA) models on 163 compounds. They report an accuracy of 0.89 on a test set of randomly selected 86 compounds.…”

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confidence: 99%

Flagging Drugs That Inhibit the Bile Salt Export Pump

et al. 2015

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The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis. Predictive computational models of BSEP inhibition may allow for fast identification of potentially harmful compounds in large databases. This article presents a predictive in silico model based on physicochemical descriptors that is able to flag compounds as potential BSEP inhibitors. This model was built using a training set of 670 compounds with available BSEP inhibition potencies. It successfully predicted BSEP inhibition for two independent test sets and was in a further step used for a virtual screening experiment. After in vitro testing of selected candidates, a marketed drug, bromocriptin, was identified for the first time as BSEP inhibitor. This demonstrates the usefulness of the model to identify new BSEP inhibitors and therefore potential cholestasis perpetrators. Just Accepted "Just Accepted" manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides "Just Accepted" as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. "Just Accepted" manuscripts appear in full in PDF format accompanied by an HTML abstract. "Just Accepted" manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). "Just Accepted" is an optional service offered to authors. Therefore, the "Just Accepted" Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the "Just Accepted" Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these "Just Accepted" manuscripts. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 Table of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 1 Flagging drugs that inhibit the bile salt export pump AbstractThe bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepa...

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“…Thus, drugs with the potential to inhibit these transporters can disturb the disposition of both co-administered drugs and bile acid, contributing to the development of cholestatic drug-induced liver injury (DILI) [42,43]. In vitro studies with isolated membrane vesicles have demonstrated an association between DILI and the inhibitory effects of drugs on bile acid efflux transporters [43][44][45]. In vitro findings may not translate directly to in vivo hepatotoxicity risk for various reasons, including complexity of bile acid homeostasis, feedback regulation of bile acid synthesis and transport, and dynamic drug/metabolite concentrations in the system [46,47].…”

Section: Pbpk For the Prediction Of Transporter-mediated Drug Inducedmentioning

confidence: 99%

Utilizing in vitro transporter data in IVIVE-PBPK: an overview

Mallick

2017

ADMET DMPK

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<p class="ADMETabstracttext">In vitro-in vivo extrapolation (IVIVE) integrated in physiologically-based pharmacokinetic (PBPK) models have been increasingly used during drug discovery and development processes to predict human pharmacokinetic (PK) parameters. Drug transporters can influence drug pharmacokinetics and are key aspects contributing to the development of a successful drug. This review provides a snapshot of challenges or shortcomings of in vitro and in vivo techniques for understanding the contribution of drug transporters to a drug’s pharmacokinetics. The paper also describes the potential of IVIVE-PBPK models as prospective approaches to predict the role of drug transporters in drug discovery and development.</p>

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Early Identification of Clinically Relevant Drug Interactions With the Human Bile Salt Export Pump (BSEP/ABCB11)

Cited by 136 publications

References 39 publications

Role of endoplasmic reticulum stress in drug‐induced toxicity

Role of endoplasmic reticulum stress in drug‐induced toxicity

Flagging Drugs That Inhibit the Bile Salt Export Pump

Utilizing in vitro transporter data in IVIVE-PBPK: an overview

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