In Vitro Metabolism of CP-122,721 ((2S,3S)-2-Phenyl-3-[(5-Trifluoromethoxy-2-Methoxy)Benzylamino]Piperidine), a Non-Peptide Antagonist of the Substance P Receptor

• Published in: DRUG METABOLISM AND PHARMACOKINETICS 2007-01, Vol.22 (5), p.336-349
• Main Authors: Scott Obach, R., Margolis, Jeannine M., Logman, Michael J.
• Format: Article
• Language: English
• Subjects: Animals; Biotransformation; CYP2D6; CYP3A4; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Dealkylation; Dogs; Enzyme Inhibitors - pharmacology; Humans; Hydroquinones - metabolism; In Vitro Techniques; Kinetics; liver microsomes; Macaca fascicularis; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Models, Biological; Molecular Structure; monoamine oxidase; Monoamine Oxidase - metabolism; neurokinin-1 antagonist; Neurokinin-1 Receptor Antagonists; O-detrifluoromethylation; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacology; Rats; Rats, Sprague-Dawley; Recombinant Proteins - metabolism; Salicylates - metabolism; Species Specificity
• ISSN: 1347-4367; 1880-0920
• DOI: 10.2133/dmpk.22.336

The metabolism of CP-122,721, a neurokinin-1 antagonist, has been examined in vitro using hepatic microsomes from human and animal species, and recombinant heterologously expressed P450 enzymes. Metabolism occurs primarily via O-demethylation and N-dealkylation reactions. In human liver microsomes, O-demethylation was shown to be catalyzed by CYP2D6 with a low KM value. N-dealkyation was shown to be catalyzed primarily by CYP3A4. When scaled to in vivo, in vitro intrinsic clearance data yielded a reasonable correlation across species. CP-122,721 was shown to be metabolized by parallel pathways to 5-trifluoromethoxysalicylic acid, which had been observed as a major circulating metabolite in humans after oral administration of CP-122,721. The involvement of CYP1A2, CYP3A4, and MAO-B was demonstrated in the pathways leading to 5-trifluoromethoxysalicylic acid. The O-desmethyl metabolite of CP-122,721 was shown to undergo a P450 catalyzed O-detrifluoromethylation reaction yielding a p-hydroquinone metabolite. The reaction was shown to be catalyzed by CYP3A4. Incubation under 18O2 yielded the hydroquinone containing O-18, consistent with this reaction occurring via an ispo substitution mechanism. Combined, these findings provide a comprehensive understanding of the metabolism of this new agent.