Danofloxacin-mesylate is a substrate for ATP-dependent efflux transporters

BACKGROUND AND PURPOSE: Next to its broad antimicrobial spectrum, the therapeutic advantages of the fluoroquinolone antimicrobial drug Danofloxacin-Mesylate (DM) are attributed to its rapid distribution to the major target tissues such as lungs, intestines and the mammary gland in animals. Previous...

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Main Authors: Schrickx, J A, Fink-Gremmels, J
Formato: Artigo
Idioma:English
Publicado em: Nature Publishing Group 2007
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Research Papers
Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC2189727/
https://ncbi.nlm.nih.gov/pubmed/17211460
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1038/sj.bjp.0706974
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spelling pubmed-21897272008-02-01 Danofloxacin-mesylate is a substrate for ATP-dependent efflux transporters Schrickx, J A Fink-Gremmels, J Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: Next to its broad antimicrobial spectrum, the therapeutic advantages of the fluoroquinolone antimicrobial drug Danofloxacin-Mesylate (DM) are attributed to its rapid distribution to the major target tissues such as lungs, intestines and the mammary gland in animals. Previous analyses revealed that effective drug concentrations are achieved also in luminal compartments of these organs, suggesting that active transport proteins facilitate excretion into the luminal space. Members of the ATP-Binding Cassette (ABC) superfamily, including P-gp, BCRP and MRP2 are known to be expressed in many tissue barriers and in cell-membranes facing luminal compartments. Hence we hypothesized that DM is a substrate for one of these efflux-transporters. EXPERIMENTAL APPROACH: Confluent monolayers of Caco-2 cells, grown on microporous membranes in two-chamber devices were used. DM concentrations were measured by fluorimetric assay after HPLC of the culture media. KEY RESULTS: DM transport across Caco-2 cells was asymmetric, with a rate of secretion exceeding that of absorption. The P-gp inhibitors PSC833 and GF120918 and the MRP-inhibitor MK571 partially decreased the secretion of DM and increased its absorption rate. The BCRP inhibitor, Ko143, decreased secretion only at a concentration of 1 μM. When DM was applied together with ciprofloxacin, secretion as well as absorption of DM decreased. CONCLUSIONS AND IMPLICATIONS: DM is a substrate for the efflux transporters P-gp and MRP2, whereas the specific role of BCRP in DM transport needs further evaluation. These findings provide a mechanistic basis for the understanding of the pharmacokinetics of DM in healthy and diseased individuals. Nature Publishing Group 2007-01-08 2007-02 /pmc/articles/PMC2189727/ /pubmed/17211460 http://dx.doi.org/10.1038/sj.bjp.0706974 Text en Copyright 2007, Nature Publishing Group
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Research Papers
spellingShingle Research Papers
Schrickx, J A
Fink-Gremmels, J
Danofloxacin-mesylate is a substrate for ATP-dependent efflux transporters
description BACKGROUND AND PURPOSE: Next to its broad antimicrobial spectrum, the therapeutic advantages of the fluoroquinolone antimicrobial drug Danofloxacin-Mesylate (DM) are attributed to its rapid distribution to the major target tissues such as lungs, intestines and the mammary gland in animals. Previous analyses revealed that effective drug concentrations are achieved also in luminal compartments of these organs, suggesting that active transport proteins facilitate excretion into the luminal space. Members of the ATP-Binding Cassette (ABC) superfamily, including P-gp, BCRP and MRP2 are known to be expressed in many tissue barriers and in cell-membranes facing luminal compartments. Hence we hypothesized that DM is a substrate for one of these efflux-transporters. EXPERIMENTAL APPROACH: Confluent monolayers of Caco-2 cells, grown on microporous membranes in two-chamber devices were used. DM concentrations were measured by fluorimetric assay after HPLC of the culture media. KEY RESULTS: DM transport across Caco-2 cells was asymmetric, with a rate of secretion exceeding that of absorption. The P-gp inhibitors PSC833 and GF120918 and the MRP-inhibitor MK571 partially decreased the secretion of DM and increased its absorption rate. The BCRP inhibitor, Ko143, decreased secretion only at a concentration of 1 μM. When DM was applied together with ciprofloxacin, secretion as well as absorption of DM decreased. CONCLUSIONS AND IMPLICATIONS: DM is a substrate for the efflux transporters P-gp and MRP2, whereas the specific role of BCRP in DM transport needs further evaluation. These findings provide a mechanistic basis for the understanding of the pharmacokinetics of DM in healthy and diseased individuals.
author Schrickx, J A
Fink-Gremmels, J
author_facet Schrickx, J A
Fink-Gremmels, J
author_sort Schrickx, J A
title Danofloxacin-mesylate is a substrate for ATP-dependent efflux transporters
title_short Danofloxacin-mesylate is a substrate for ATP-dependent efflux transporters
title_full Danofloxacin-mesylate is a substrate for ATP-dependent efflux transporters
title_fullStr Danofloxacin-mesylate is a substrate for ATP-dependent efflux transporters
title_full_unstemmed Danofloxacin-mesylate is a substrate for ATP-dependent efflux transporters
title_sort danofloxacin-mesylate is a substrate for atp-dependent efflux transporters
publisher Nature Publishing Group
publisher_facet Nature Publishing Group
publishDate 2007
url https://ncbi.nlm.nih.gov/pmc/articles/PMC2189727/
https://ncbi.nlm.nih.gov/pubmed/17211460
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1038/sj.bjp.0706974
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