Studies on the interaction between inhaled drug molecules and mucin

Giorgetti, Melania (2016) Studies on the interaction between inhaled drug molecules and mucin. Doctoral thesis, University of East Anglia.

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Abstract

Mucus is a dynamic gel network primarily composed of water. The principal
“non-water” component of mucus is mucin, a macromolecular glycoprotein largely
responsible for the viscoelastic gel nature of mucus. Recent evidence indicates that
some inhaled antibiotics are bound by mucus components and their biological
activity reduced.
This thesis focussed upon the mucin binding of a panel of epithelial sodium
channel (ENaC) blockers that have been studied as experimental therapeutic agents
for cystic fibrosis (CF). Using porcine gastric mucin (PGM) as a model system the
directional transport of FL-Na, FITC dextran probes (4-70 kDa) and two ENaC blockers
was determined using Franz diffusion cells. Size-dependent restriction of dextran
transport was accompanied by a large disparity in the passage of two structurally
similar ENaC blockers with differing lipophilic character. A 96-well ultrafiltration assay
was developed to study mucin-binding of 12 related ENaC blockers of two main
structural groups: quaternary amine compounds (QQA) and non-quaternary amine
(NQQA) analogues. The extent of binding was variable within sub-groups and
correlated well with Log P o/w. Other physical parameters (e.g. rotatable bond
number, PSA) served as good correlates only for QQA structures. In contrast, the
apical-basolateral transport of ENaC blockers across restrictive Calu-3 monolayers
was not clearly predicated by solute hydrophobicity. Saturation Transfer Difference
(STD)-NMR spectroscopy was used to gather structural details of mucin-drug
interactions. These studies provide the first evidence that STD-NMR can be used to
identify discrete molecular regions that participate in interactions with mucin.
In conclusion, these data indicate that some inhaled drugs undergo reversible
interactions with mucus. This finding could have wide implications for the design of
new inhaled therapies for lung diseases where binding to supraphysiological amounts
of airway mucus may modulate drug disposition and clinical response.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Katie Miller
Date Deposited: 25 May 2017 15:18
Last Modified: 25 May 2017 15:18
URI: https://ueaeprints.uea.ac.uk/id/eprint/63610
DOI:

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