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.
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 K(M) 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 (18)O(2) 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.
Obach
R Scott
RS
Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Global Research and Development, Pfizer Inc, Groton, CT 06340, USA. r.scott.obach@pfizer.com
Margolis
Jeannine M
JM
Logman
Michael J
MJ
D000818:Animals; D001711:Biotransformation; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003640:Dealkylation; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D012459:Salicylates / Q000378:metabolism; D013045:Species Specificity
C521751:5-trifluoromethoxysalicylic acid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011994:Recombinant Proteins; D012459:Salicylates; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D008995:Monoamine Oxidase; C099414:(2S,3S)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine