Linaclotide, a synthetic
guanylyl cyclase C (GC-C) agonist, and the prostone analog,
Lubiprostone, are approved to manage chronic idiopathic
constipation and
constipation-predominant
irritable bowel syndrome.
Lubiprostone also protects intestinal mucosal barrier function in
ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect
linaclotide and
lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with
linaclotide,
lubiprostone, or vehicle to determine effects on short-circuit current (I sc). Subsequent I sc responses to the cAMP agonist,
forskolin, and the
calcium agonist,
carbachol, were also measured to assess if either
drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. I sc responses to
linaclotide and
lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of
linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to
forskolin.
Lubiprostone reduced
forskolin responses under all conditions.
Linaclotide and
lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen.
Linaclotide and
lubiprostone increase ion transport responses across normal human colon but
linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with
constipation.