Does mucin binding have an effect on the inhaled disposition of ENaC blockers?

Melania Giorgetti, Jesus Angulo, Nichola Smith, Brian Cox, David Sandham, Chris Morris

Mucus is a key component of the pulmonary mucosal defence system trapping inspired microorganisms and particulate material. The main “non-water” component of mucus is the macromolecular glycoprotein, mucin, which is principally responsible for the viscoelastic gel nature of mucus. Mucin forms a complex gel network that presents both polar glycosylated domains and un-glycosylated non-polar domains that may serve as drug binding pockets. Indeed, evidence suggests that some inhaled drug molecules can be bound by mucus and their diffusion rate significantly retarded. In this work we examined the mucin binding of a panel of inhaled drug candidates with the aim of identifying the key drug physicochemical parameters which predict mucin binding.
We present data for the mucin binding of a panel of epithelial sodium channel (ENaC) blockers, including amiloride and its analogues, which have been studied as experimental therapeutics for cystic fibrosis (CF). Ultrafiltration binding assays were performed to examine the binding characteristics for a panel of analogues which spanned a log P and molecular weight range of -0.89 to 1.45 and 230 to 756, respectively. A strong positive correlation was observed between the extent of binding and drug log P, whereas parameters such as molecular weight, polar surface area and molecular volume were weakly predictive of mucin binding. Molecular level information about these drug-mucin interactions was obtained from Saturation Transfer Difference-NMR spectroscopy studies. These studies identified “interacting” and “non-interacting” domains within the drug molecule. The study highlights the potential for mucin to impact upon drug disposition in the lung.

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