Metabolism and excretion of CP-122,721, a non-peptide antagonist of the neurokinin NK1 receptor, in dogs: Identification of the novel cleaved product 5-trifluoromethoxy salicylic acid in plasma

Abstract

The metabolism and excretion of a potent and selective substance P receptor antagonist, CP-122,721, have been studied in beagle dogs following oral administration of a single 5 mg kg⁻¹ dose of [¹⁴C]CP-122,721. Total recovery of the administered dose was on average 89% for male dogs and 95% for female dogs. Approximately 94% of the radioactivity recovered in urine and feces was excreted in the first 72 h. Male bile duct-cannulated dogs excreted a mean of ∼56% of the dose in bile, ∼11% in feces, and ∼25% in urine. The sum of radioactivity in bile and urine indicates >80% of the [¹⁴C]CP-122,721-derived radioactivity was absorbed by the gastrointestinal tract. CP-122,721 was extensively metabolized in dogs, and only a small amount of parent CP-122,721 was excreted as unchanged drug. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or feces. The major metabolic pathways of CP-122,721 were O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included: Aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, and N-dealkylation with subsequent sulfation and/or oxidative deamination. In addition, the novel cleaved product 5-trifluoromethoxy salicylic acid (TFMSA) was identified in plasma. These results suggest that dog is the most relevant animal species in which the metabolism of CP-122,721 can be studied for extrapolating the results to humans.

Key Words::

• Biotransformation
• metabolism
• CP-122,721
• trifluoromethoxy anisole
• NK1 receptor antagonist
• dogs
• LC-MS/MS
• conjugates
• 5-trifluoromethoxy salicylic acid (TFMSA)