Membrane Vesicle ABC Transporter Assays for Drug Safety Assessment

Staden, Carlo J. van; Morgan, Ryan E.; Ramachandran, Bharath; Chen, Yuan; Lee, Paul H.; Hamadeh, Hisham K.

doi:10.1002/0471140856.tx2305s54

Cited by 23 publications

(16 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the IC 50 values for the remaining TKIs evaluated by Morgan, et al were notably different, which may reflect differences in the experimental conditions such as the specific transporter substrate and range of inhibitor concentrations selected for investigation (e.g. extrapolation of an IC 50 value beyond the tested concentrations) [35,36]. The majority of the potent MRP4 inhibitors fell within the EGFR TKI class with only one potent inhibitor each in the dual VEGFR & PDGFR and the BCR/ABL classes.…”

Section: Resultsmentioning

confidence: 99%

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

et al. 2016

View full text Add to dashboard Cite

Tyrosine and aurora kinases are important effectors in signal transduction pathways that are often involved in aberrant cancer cell growth. Tyrosine (TKI) and aurora (AKI) kinase inhibitors are anti-cancer MRP4: alisertib, danusertib, erlotinib, lapatinib, neratinib, nilotinib, pazopanib, sorafenib, and tozasertib. The potentially clinically relevant inhibition of BCRP was much more extensive and included alisertib, barasertib, danusertib, enzastaurin, erlotinib, gefitinib, imatinib, neratinib, nilotinib, pazopanib, selumetinib, sorafenib, sunitinib, tozasertib, and vandetanib Keywords ABC transporters; transport inhibition ADMET & DMPK 4(4) (2016) 302-313TKIs and AKIs diminish transport of function of MRP4 and BCRP

show abstract

Section: Resultsmentioning

confidence: 99%

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

et al. 2016

View full text Add to dashboard Cite

show abstract

“…This corresponds to true zero-trans conditions. In contrast, as described in details by van Staden and co-workers 48 , Morgan et al start the uptake by adding ATP to vesicles pre-incubated with both substrate and inhibitors. This pre-incubation leads most likely to a deviation from a true zero-trans condition, which is needed for this type of transport experiment.…”

Section: Discussionmentioning

confidence: 99%

Flagging Drugs That Inhibit the Bile Salt Export Pump

et al. 2015

View full text Add to dashboard Cite

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...

show abstract

“…The [ 14 C] AMG 416 direct uptake assay was conducted in HEK293 cells transfected with organic anion transporter (OAT) 1, OAT3, OAT polypeptide (OATP) 1B1, OATP1B3, peptide transporter 1, 2, or organic cation transporter (OCT) 2 transporter (Yamazaki et al, 2005;Chu et al, 2007). The effect of AMG 416 on human bile salt export pump (BSEP) transporter was evaluated according to a published method (van Staden et al, 2012 In Vivo Methods Study Design. The study overview is outlined in Table 1, and the individual experiment details are provided as follows under the respective group identifier.…”

Section: In Vitro Methodsmentioning

confidence: 99%

Nonclinical Pharmacokinetics, Disposition, and Drug-Drug Interaction Potential of a Novel D-Amino Acid Peptide Agonist of the Calcium-Sensing Receptor AMG 416 (Etelcalcetide)

Subramanian

Zhu

Kerr

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

AMG 416 (etelcalcetide) is a novel synthetic peptide agonist of the calcium-sensing receptor composed of a linear chain of seven D-amino acids (referred to as the D-amino acid backbone) with a D-cysteine linked to an L-cysteine via a disulfide bond. AMG 416 contains four basic D-arginine residues and is a +4 charged peptide at physiologic pH with a mol. wt. of 1048.3 Da. The pharmacokinetics (PK), disposition, and potential of AMG 416 to cause drug-drug interaction were investigated in nonclinical studies with two single 14 C-labels placed either at a potentially metabolically labile acetyl position or on the D-alanine next to D-cysteine in the interior of the D-amino acid backbone. After i.v. dosing, the PK and disposition of AMG 416 were similar in male and female rats. Radioactivity rapidly distributed to most tissues in rats with intact kidneys, and renal elimination was the predominant clearance pathway. No straindependent differences were observed. In bilaterally nephrectomized rats, minimal radioactivity (1.2%) was excreted via nonrenal pathways. Biotransformation occurred primarily via disulfide exchange with endogenous thiol-containing molecules in whole blood rather than metabolism by enzymes, such as proteases or cytochrome P450s; the D-amino acid backbone remained unaltered. A substantial proportion of the plasma radioactivity was covalently conjugated to albumin. AMG 416 presents a low risk for P450 or transportermediated drug-drug interactions because it showed no interactions in vitro. These studies demonstrated a 14 C label on either the acetyl or the D-alanine in the D-amino acid backbone would be appropriate for clinical studies.

show abstract

Membrane Vesicle ABC Transporter Assays for Drug Safety Assessment

Cited by 23 publications

References 61 publications

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

Flagging Drugs That Inhibit the Bile Salt Export Pump

Nonclinical Pharmacokinetics, Disposition, and Drug-Drug Interaction Potential of a Novel D-Amino Acid Peptide Agonist of the Calcium-Sensing Receptor AMG 416 (Etelcalcetide)

Contact Info

Product

Resources

About