Evidence map›Paper›PMID 31180118›Full record

ArticleThe Journal of infectious diseases2019

P-Glycoprotein-Mediated Efflux Reduces the In Vivo Efficacy of a Therapeutic Targeting the Gastrointestinal Parasite Cryptosporidium.

Samuel L M Arnold, Ryan Choi, Matthew A Hulverson, Grant R Whitman, Molly C Mccloskey, Carlie S Dorr, Rama S R Vidadala, Mansi Khatod, Mary Morada, Lynn K Barrett and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of infectious diseases, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
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

6 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Article
  5. Review
  6. Setting Our Sights on Infectious Diseases.ACS infectious diseases · 2020
    Article
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

13 authors.

Samuel L M ArnoldDivision of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle.
Ryan ChoiDivision of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle.
Matthew A HulversonDivision of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle.
Grant R WhitmanDivision of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle.
Molly C MccloskeyDivision of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle.
Carlie S DorrDivision of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle.
Rama S R VidadalaDepartment of Chemistry, University of Washington, Seattle.
Mansi KhatodPace University, New York, New York.
Mary MoradaPace University, New York, New York.
Lynn K BarrettDivision of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle.
Dustin J MalyDepartment of Chemistry, University of Washington, Seattle.
Nigel YarlettPace University, New York, New York.
Wesley C Van VoorhisDivision of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle.

Funding

Bumped Kinase Inhibitors: Novel Therapeutics for Cryptosporidiosis&ToxoplasmosisR01AI111341 · NIAID · UNIVERSITY OF WASHINGTON · PI VAN VOORHIS, WESLEY C · 2014 to 2018
$6.4M
Calcium Dependent Protein Kinase 1 as a drug target for T. gondii and C. parvumR01AI089441 · NIAID · UNIVERSITY OF WASHINGTON · PI MERRITT, ETHAN A, PARSONS, MARILYN · 2010 to 2014
$5.0M
Dual Use Therapeutics for Cryptosporidiosis, Toxoplasmosis, and NeosporosisR01HD080670 · NICHD · UNIVERSITY OF WASHINGTON · PI VAN VOORHIS, WESLEY C · 2014 to 2018
$1.9M
NIAID NIH HHS R01 AI089441NIAID NIH HHS R01 AI111341NICHD NIH HHS R01 HD080670
6 · The paper itself

Abstract

Recent studies have illustrated the burden Cryptosporidium infection places on the lives of malnourished children and immunocompromised individuals. Treatment options remain limited, and efforts to develop a new therapeutic are currently underway. However, there are unresolved questions about the ideal pharmacokinetic characteristics of new anti-Cryptosporidium therapeutics. Specifically, should drug developers optimize therapeutics and formulations to increase drug exposure in the gastrointestinal lumen, enterocytes, or systemic circulation? Furthermore, how should researchers interpret data suggesting their therapeutic is a drug efflux transporter substrate? In vivo drug transporter-mediated alterations in efficacy are well recognized in multiple disease areas, but the impact of intestinal transporters on therapeutic efficacy against enteric diseases has not been established. Using multiple in vitro models and a mouse model of Cryptosporidium infection, we characterized the effect of P-glycoprotein efflux on bumped kinase inhibitor pharmacokinetics and efficacy. Our results demonstrated P-glycoprotein decreases bumped kinase inhibitor enterocyte exposure, resulting in reduced in vivo efficacy against Cryptosporidium. Furthermore, a hollow fiber model of Cryptosporidium infection replicated the in vivo impact of P-glycoprotein on anti-Cryptosporidium efficacy. In conclusion, when optimizing drug candidates targeting the gastrointestinal epithelium or gastrointestinal epithelial infections, drug developers should consider the adverse impact of active efflux transporters on efficacy.

Indexed as

AnimalsATP Binding Cassette Transporter, Subfamily B, Member 1Biological Transport, ActiveCaco-2 CellsCell Membrane PermeabilityCryptosporidiosisCryptosporidiumDisease Models, AnimalDrug DiscoveryEnterocytesFemaleGastrointestinal AbsorptionHumansInterferon-gammaIntestinal Diseases, ParasiticMiceATP Binding Cassette Transporter, Subfamily B, Member 1BKI 1369bumped kinase inhibitor 1294IFNG protein, mouseInterferon-gammaNaphthalenesPiperidinesPyrazolesPyrimidinesQuinolinesCryptosporidiumdrug developmentdrug effluxentericgastrointestinalP-gp

Identifiers

PMID31180118
PMCPMC6736360

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.