Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S)] has been shown to be a potent and selective antagonist of the human neurokinin 1 receptor, the primary receptor for substance P. During long-term toxicity studies conducted in rat and dog, evidence of cardiomyopathy and increased cardiac weight were observed. The distribution and metabolism of casopitant were studied in both species evaluating the accumulation of drug-related material (DRM) after repeat dosing and its potential relationship with pathological findings observed in myocardium. After repeat oral administration of [(14)C]casopitant to rats (20 days) and dogs (14 days), DRM was quantifiable in all of the tissues examined with lung and liver containing the highest level of radioactivity. The concentration of radioactivity was significantly higher in tissues than in plasma, declining slowly and still quantifiable after a recovery period of 20 days. The principal circulating components identified in both species were casopitant, M12 (oxidized deacetylated), M13 (hydroxylated piperazine), and M31 and M134 (two N-dealkylated piperazines). In tissues, a similar metabolic pattern was observed, in which casopitant, M31, M134, M76 (N-deacetylated), and M200 (N-deacetylated N,N-deethylated) were the major components quantified. After a 26-week repeat dose study in dog, casopitant and M13 were the major circulating components, whereas in myocardium, M200 and M134 were the major ones and their levels increased over time, reaching considerable concentrations (millimolar magnitude). After a washout period, all circulating derivatives decreased to undetectable levels, whereas M200 was still the major component in myocardium. Overall DRM in plasma did not correlate with the respective concentrations in tissues.
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PMID:Tissue distribution and characterization of drug-related material in rats and dogs after repeated oral administration of casopitant. 2097 4

Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S), GW679769] has previously been shown to be a potent and selective antagonist of the human neurokinin-1 receptor, the primary receptor of substance P, both in vitro and in vivo, with good brain penetration properties. On the basis of this mode of action it was evaluated for the prevention of chemotherapy-induced and postoperative nausea and vomiting, and for the chronic treatment of anxiety, depression, insomnia, and overactive bladder. Casopitant is shown to be a substrate, an inhibitor, and an inducer of CYP3A4, and, because of this complex behavior, it was difficult to identify the primary mechanism by which it may give rise to drug-drug interactions (DDIs) of clinical relevance. Moreover, the major circulating metabolite is itself an inhibitor of CYP3A4 in vitro. On the basis of the different clinical indications and the various potential comedications of casopitant, a relevant part of the clinical development plan was focused on the assessment of the importance of clinical DDIs. The present study provides an overview of the DDI potential profile of casopitant, based on in vitro data and clinical evidence of its interaction with CYP3A4 probe substrates midazolam and nifedipine, the strong inhibitor ketoconazole, and the inducer rifampin. Overall, the clinical data confirm the ability of casopitant to interact with CYP3A4 substrates, inhibitors, or inducers. The in vitro data are accurate and robust enough to build a reliable SimCyp population-based model to estimate the potential DDIs of casopitant and to minimize the clinical studies recommended.
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PMID:Casopitant: in vitro data and SimCyp simulation to predict in vivo metabolic interactions involving cytochrome P450 3A4. 2114 41