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

A small-molecule inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR), 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTRinh-172), reduces enterotoxin-induced intestinal fluid secretion in rodents. Here, we study CFTRinh-172 pharmacology and antidiarrheal efficacy in rodents using C-14-labeled CFTRinh-172, liquid chromatography/mass spectrometry, and a closed intestinal loop model of fluid secretion. CFTRinh-172 was cleared primarily by renal glomerular filtration without chemical modification. CFTRinh-172 accumulated in liver within 5 min after intravenous infusion in mice, and was concentrated fivefold in bile over blood. At 30-240 min, CFTRinh-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. CFTRinh-172 was stable in hepatic microsomes. Closed-loop studies in mice indicated that a single intraperitoneal injection of 20 mug CFTRinh-172 inhibited fluid accumulation at 6 h after cholera toxin by >90% in duodenum and jejunum, similar to60% in ileum and <10% in colon. No toxicity was seen after high-dose CFTRinh-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 CFTRinh-172 account for its efficacy as an antidiarrheal. (C) 2004 Wiley-Liss, Inc.