title: In vivo pharmacology and antidiarrheal efficacy of a thiazolidinone CFTR inhibitor in rodents.
abstract: 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.
authors.affiliation: Department of Medicine, Cardiovascular Research Institute, 1246 Health Sciences East Tower, University of California, San Francisco, California 94143-0521, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: Sonawane
authors.forename: Chatchai
authors.initials: C
authors.lastname: Muanprasat
authors.forename: Ray
authors.initials: R
authors.lastname: Nagatani
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Song
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D000930:Antidiarrheals / Q000493:pharmacokinetics / Q000494:pharmacology*; D001345:Autoradiography; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D006207:Half-Life; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D000930:Antidiarrheals; D007202:Indicators and Reagents; D013844:Thiazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator