The cystic fibrosis transmembrane conductance regulator (CFTR) provides an important apical route for Cl⁻ secretion across intestinal epithelia. A thiazolidinone-type CFTR blocker (CFTR_inh-172) reduced cholera toxin-induced fluid accumulation in mouse intestinal loops. Here, we characterize the efficacy and pharmacodynamics of CFTR_inh-172 in blocking cAMP and cGMP induced Cl⁻/fluid secretion in rodent and human intestine.

CFTR_inh-172 inhibited cAMP and cGMP agonist induced short-circuit current by >95% in T84 colonic epithelial cells (K_I ∼ 3 μmol/L) and in mouse and human intestinal sheets (K_I ∼ 9 μmol/L). A single intraperitoneal injection of CFTR_inh-172 (200 μg) blocked intestinal fluid secretion in a rat closed-loop model by >90% for cholera toxin and >70% for STa Escherichia coli toxin. In mice, CFTR_inh-172 (20 μg) inhibited cholera toxin-induced intestinal fluid secretion by 90% (persistence t_1/2 ∼10 hours, K_I ∼ 5 μg) and STa toxin by 75% (K_I ∼ 10 μg). Tissue distribution and pharmacokinetic studies indicated intestinal CFTR_inh-172 accumulation facilitated by enterohepatic circulation. An oral CFTR_inh-172 preparation reduced fluid secretion by >90% in a mouse open-loop cholera model.

A small molecule CFTR blocker markedly reduced intestinal ion and fluid secretion caused by cAMP/cGMP-dependent bacterial enterotoxins. CFTR inhibition may thus reduce fluid secretion in infectious secretory diarrheas.