title: Safety concerns over the use of intestinal permeation enhancers: A mini-review.
abstract: Intestinal permeation enhancers (PEs) are key components in ∼12 oral peptide formulations in clinical trials for a range of molecules, primarily insulin and glucagon-like-peptide 1 (GLP-1) analogs. The main PEs comprise medium chain fatty acid-based systems (sodium caprate, sodium caprylate, and N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC)), bile salts, acyl carnitines, and EDTA. Their mechanism of action is complex with subtle differences between the different molecules. With the exception of SNAC and EDTA, most PEs fluidize the plasma membrane causing plasma membrane perturbation, as well as enzymatic and intracellular mediator changes that lead to alteration of intestinal epithelial tight junction protein expression. The question arises as to whether PEs can cause irreversible epithelial damage and tight junction openings sufficient to permit co-absorption of payloads with bystander pathogens, lipopolysaccharides and its fragment, or exo- and endotoxins that may be associated with sepsis, inflammation and autoimmune conditions. Most PEs seem to cause membrane perturbation to varying extents that is rapidly reversible, and overall evidence of pathogen co-absorption is generally lacking. It is unknown however, whether the intestinal epithelial damage-repair cycle is sustained during repeat-dosing regimens for chronic therapy.
authors.affiliation: UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin , Belfield, Dublin 4, Ireland.
authors.forename: Fiona
authors.initials: F
authors.lastname: McCartney
authors.affiliation: UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin , Belfield, Dublin 4, Ireland.
authors.forename: John P
authors.initials: JP
authors.lastname: Gleeson
authors.affiliation: UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin , Belfield, Dublin 4, Ireland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brayden
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D003652:Decanoic Acids / Q000009:adverse effects / Q000737:chemistry; D004337:Drug Carriers / Q000009:adverse effects* / Q000737:chemistry; D006801:Humans; D007408:Intestinal Absorption
chemical_list: D003652:Decanoic Acids; D004337:Drug Carriers
keywords: SNAC; epithelial toxicity; intestinal permeation enhancers; medium chain fatty acids; oral peptide delivery; sodium caprate