In vivo pharmacology and antidiarrheal efficacy of a thiazolidinone CFTR inhibitor in rodents

J Pharm Sci. 2005 Jan;94(1):134-43. doi: 10.1002/jps.20228.


A small-molecule inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR), 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTR(inh)-172), reduces enterotoxin-induced intestinal fluid secretion in rodents. Here, we study CFTR(inh)-172 pharmacology and antidiarrheal efficacy in rodents using (14)C-labeled CFTR(inh)-172, liquid chromatography/mass spectrometry, and a closed intestinal loop model of fluid secretion. CFTR(inh)-172 was cleared primarily by renal glomerular filtration without chemical modification. CFTR(inh)-172 accumulated in liver within 5 min after intravenous infusion in mice, and was concentrated fivefold in bile over blood. At 30-240 min, CFTR(inh)-172 was found mainly in liver, intestine, and kidney, with little detectable in the brain, heart, skeletal muscle, or lung. Pharmacokinetic analysis in rats following intravenous bolus infusion showed a distribution volume of 770 mL with redistribution and elimination half-times of 0.14 h and 10.3 h, respectively. CFTR(inh)-172 was stable in hepatic microsomes. Closed-loop studies in mice indicated that a single intraperitoneal injection of 20 microg CFTR(inh)-172 inhibited fluid accumulation at 6 h after cholera toxin by >90% in duodenum and jejunum, approximately 60% in ileum and <10% in colon. No toxicity was seen after high-dose CFTR(inh)-172 administration (3 mg/kg/day in two daily doses) in mice over the first 6 weeks of life. The metabolic stability, enterohepatic recirculation, slow renal elimination, and intestinal accumulation of CFTR(inh)-172 account for its efficacy as an antidiarrheal.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antidiarrheals / pharmacokinetics
  • Antidiarrheals / pharmacology*
  • Autoradiography
  • Biotransformation
  • Chromatography, High Pressure Liquid
  • Chromatography, Thin Layer
  • Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors*
  • Half-Life
  • In Vitro Techniques
  • Indicators and Reagents
  • Intestinal Mucosa / metabolism
  • Male
  • Mass Spectrometry
  • Mice
  • Microsomes, Liver / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology*
  • Tissue Distribution


  • Antidiarrheals
  • Indicators and Reagents
  • Thiazoles
  • Cystic Fibrosis Transmembrane Conductance Regulator