In Vivo Pharmacology and Antidiarrheal Efficacy of a Thiazolidinone 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 14C‐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 μg CFTRinh‐172 inhibited fluid accumulation at 6 h after cholera toxin by >90% in duodenum and jejunum, ∼60% 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.