title: Evaluation of calcium depletion as a strategy for enhancement of mucosal absorption of macromolecules.
abstract: Extracellular calcium is crucial for functioning of the epithelial barrier. Compounds that bind calcium, reducing its extracellular levels, have therefore been investigated as mucosal absorption enhancers. However, the conditions under which calcium reduction sufficiently modulates the epithelial barrier to result in meaningful improvements in mucosal drug absorption are unclear. Present work investigated the settings in which calcium depletion leads to optimal epithelial barrier-modulating effects. Using Calu-3 and Caco-2 cell layers and inducing calcium depletion site-specifically (apically, basolaterally or on both sides) we demonstrate that apical calcium removal produces a modest effect on the tight junctions (the extent of the effect being dependent on the duration of apical calcium unavailability), whilst basolateral calcium exhaustion leads to a prominent effect on the epithelial barrier. However, using polyacrylic acid as an example, we show that polymeric calcium-binding agents proposed as mucosal absorption-enhancing excipients alter calcium levels exclusively on the apical side of the epithelium, which explains their modest effect on epithelial barrier modulation (also demonstrated in our work). Therefore the use of calcium-depleting agents, especially those based on macromolecular polymers, is a relatively inefficacious strategy to promote mucosal absorption of macromolecules.
authors.affiliation: Division of Drug Delivery and Tissue Engineering, Boots Science Building, University of Nottingham, University Park, Nottingham NG7 2RD, UK. Driton.Vllasaliu@nottingham.ac.uk
authors.forename: Driton
authors.initials: D
authors.lastname: Vllasaliu
authors.forename: Saif
authors.initials: S
authors.lastname: Shubber
authors.forename: Martin
authors.initials: M
authors.lastname: Garnett
authors.forename: Cameron
authors.initials: C
authors.lastname: Alexander
authors.forename: Mike
authors.initials: M
authors.lastname: Eaton
authors.forename: Snow
authors.initials: S
authors.lastname: Stolnik
mesh_terms: D000042:Absorption / Q000187:drug effects; D000180:Acrylic Resins / Q000494:pharmacology; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism*; D016503:Drug Delivery Systems; D006801:Humans; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism*; D010599:Pharmacokinetics; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000180:Acrylic Resins; C006903:carbopol 940; D002118:Calcium