Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor.
OBJECTIVE
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.


RESULTS
CFTR(inh)-172 inhibited cAMP and cGMP agonist induced short-circuit current by >95% in T84 colonic epithelial cells (K(I) approximately 3 micromol/L) and in mouse and human intestinal sheets (K(I) approximately 9 micromol/L). A single intraperitoneal injection of CFTR(inh)-172 (200 microg) 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 microg) inhibited cholera toxin-induced intestinal fluid secretion by 90% (persistence t(1/2) approximately 10 hours, K(I) approximately 5 microg) and STa toxin by 75% (K(I) approximately 10 microg). 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.


CONCLUSIONS
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.
Thiagarajah
Jay R
JR
Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, 94143, USA.
Broadbent
Talmage
T
Hsieh
Emily
E
Verkman
Alan S
AS
D000284:Administration, Oral; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001826:Body Fluids / Q000187:drug effects*; D002460:Cell Line; D002712:Chlorides / Q000037:antagonists & inhibitors*; D002772:Cholera Toxin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000819:agonists; D006152:Cyclic GMP / Q000819:agonists; D004553:Electric Conductivity; D004768:Enterotoxins / Q000494:pharmacology*; D029968:Escherichia coli Proteins; D006801:Humans; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects*; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D053778:Thiazolidines; D014018:Tissue Distribution
C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001427:Bacterial Toxins; D001565:Benzoates; D002712:Chlorides; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D007473:Ion Channels; D013844:Thiazoles; D053778:Thiazolidines; C034151:heat stable toxin (E coli); D002772:Cholera Toxin; D000242:Cyclic AMP; D006152:Cyclic GMP