Evidence map›Paper›PMID 23397054›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2013

Saturable active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier leads to nonlinear distribution of elacridar to the central nervous system.

Ramola Sane, Sagar Agarwal, Rajendar K Mittapalli, William F Elmquist

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed
2.2field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

26 citing papers in PubMed, 44 citations in OpenAlex.

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  18. Pantoprazole Induces Apoptosis of Leukemic Cells by Inhibiting Expression of P-Glycoprotein/Multidrug Resistance-Associated Protein-1 Through PI3K/AKT/mTOR Signaling.Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion · 2017
    Article
  19. Renal Drug Transporters and Drug Interactions.Clinical pharmacokinetics · 2017
    Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors at 1 institution in 1 country.

Ramola SaneDepartment of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Sagar Agarwal
Rajendar K Mittapalli
William F Elmquist
University of Minnesota · US

Funding

Improving Delivery of Molecularly-Targeted Therapy to Invasive Glioma CellsR01CA138437 · NCI · UNIVERSITY OF MINNESOTA · PI ELMQUIST, WILLIAM, OHLFEST, JOHN R · 2010 to 2014
$1.5M
NCI NIH HHS CA138437NCI NIH HHS R01 CA138437
6 · The paper itself

Abstract

The study objective was to investigate factors that affect the central nervous system (CNS) distribution of elacridar. Elacridar inhibits transport mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) and has been used to study the influence of transporters on brain distribution of chemotherapeutics. Adequate distribution of elacridar across the blood-brain barrier (BBB) and into the brain parenchyma is necessary to target tumor cells in the brain that overexpress transporters and reside behind an intact BBB. We examined the role of P-gp and Bcrp on brain penetration of elacridar using Friend leukemia virus strain B wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice. Initially, the mice were administered 2.5 mg/kg of elacridar intravenously, and the plasma and brain concentrations were determined. The brain-to-plasma partition coefficient of elacridar in the wild-type mice was 0.82, as compared with 3.5 in Mdr1a/b(-/-) mice, 6.6 in Bcrp1(-/-) mice, and 15 in Mdr1a/b(-/-)Bcrp1(-/-) mice, indicating that both P-gp and Bcrp limit the brain distribution of elacridar. The four genotypes were then administered increasing doses of elacridar, and the CNS distribution of elacridar was determined. The observed and model predicted maximum brain-to-plasma ratios (Emax) at the highest dose were not significantly different in all genotypes. However, the ED50 was lower for Mdr1a/b(-/-) mice compared with Bcrp1(-/-) mice. These findings correlate with the relative expression of P-gp and Bcrp at the BBB in these mice and demonstrate the quantitative enhancement in elacridar CNS distribution as a function of its dose. Overall, this study provides useful concepts for future applications of elacridar as an adjuvant therapy to improve targeting of chemotherapeutic agents to tumor cells in the brain parenchyma.

Indexed as

AcridinesAnimalsATP-Binding Cassette Sub-Family B Member 4ATP-Binding Cassette TransportersATP Binding Cassette Transporter, Subfamily BATP Binding Cassette Transporter, Subfamily B, Member 1ATP Binding Cassette Transporter, Subfamily G, Member 2Blood-Brain BarrierCell Culture TechniquesCentral Nervous SystemDogsDose-Response Relationship, DrugHumansInjections, IntravenousMadin Darby Canine Kidney CellsMiceABCB1 protein, humanAbcg2 protein, mouseAcridinesATP-Binding Cassette Sub-Family B Member 4ATP-Binding Cassette TransportersATP Binding Cassette Transporter, Subfamily BATP Binding Cassette Transporter, Subfamily B, Member 1ATP Binding Cassette Transporter, Subfamily G, Member 2Elacridarmultidrug resistance protein 3Tetrahydroisoquinolines

Identifiers

PMID23397054
PMCPMC3608446
OpenAlexW2143847158

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.