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

Autor: Rama Subba Rao Vidadala, Grant R. Whitman, Carlie S. Dorr, Molly C. McCloskey, Ryan Choi, Mansi Khatod, Samuel L.M. Arnold, Mary Morada, Wesley C. Van Voorhis, Nigel Yarlett, Dustin J. Maly, Lynn K. Barrett, Matthew A. Hulverson
Rok vydání: 2019
Předmět:
0301 basic medicine
Cell Membrane Permeability
Cryptosporidiosis
Pharmacology
Mice
Piperidines
Drug Discovery
Immunology and Allergy
Medicine
Intestinal Diseases
Parasitic
P-glycoprotein
media_common
Mice
Knockout
biology
Cryptosporidium
drug efflux
3. Good health
Treatment Outcome
Infectious Diseases
Drug development
Quinolines
Female
Efflux
Drug
media_common.quotation_subject
030106 microbiology
Biological Transport
Active
Naphthalenes
Gastrointestinal epithelium
Major Articles and Brief Reports
Interferon-gamma
03 medical and health sciences
Pharmacokinetics
In vivo
Animals
Humans
Parasites
ATP Binding Cassette Transporter
Subfamily B
Member 1
business.industry
enteric
biology.organism_classification
gastrointestinal
drug development
Disease Models
Animal
Enterocytes
Pyrimidines
030104 developmental biology
Gastrointestinal Absorption
biology.protein
P-gp
Pyrazoles
Caco-2 Cells
business
Zdroj: The Journal of Infectious Diseases
ISSN: 1537-6613
0022-1899
Popis: 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.
How intestinal P-glycoprotein drug efflux affects therapeutics targeting intestinal pathogens was not clear. For bumped kinase inhibitors targeting Cryptosporidium, P-glycoprotein reduces the therapeutic enterocyte exposure, and this is associated with reduced in vivo efficacy in a mouse model of cryptosporidiosis.
Databáze: OpenAIRE
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