Tissue distribution and characterization of drug-related material in rats and dogs after repeated oral administration of casopitant.

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.

Metabolic disposition of casopitant, a potent neurokinin-1 receptor antagonist, in mice, rats, and dogs.

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)] is a potent and selective antagonist of the neurokinin-1 (NK1) receptor, developed for the prevention of chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting. Absorption, distribution, metabolism, and elimination of [(14)C]casopitant have been investigated in the mouse, rat, and dog after single oral administration and compared with those in humans. [(14)C]Casopitant was rapidly absorbed in all three species: the maximum plasma concentration of radioactivity was generally observed 0.5 to 2 h after a single oral dose. In dog and female rat, as observed for humans, the principal circulating radiolabeled components were unchanged casopitant and its hydroxylated derivative M13. In rats, there was an evident sex-related difference in the rate of elimination of drug-related material with elimination being more rapid in males than in females. In dogs and mice, no notable sex differences were observed in the pattern of excretion. The elimination of drug-related radioactivity was largely by metabolism, with metabolites excreted primarily in the feces. The predominant route of metabolism was the oxidation of the parent molecule, observed together with loss of the N-acetyl group, N-demethylation, and modification of piperazine with consequent opening and cleavage of the ring, giving a complex pattern of metabolites. Conjugation of some of those oxidized products with glucuronic acid was observed. Urinary excretion in all three species was a minor route of elimination, accounting for between 2 and 7% of the dose, with unchanged parent drug never quantifiable.

Disposition and metabolism of radiolabeled casopitant in humans.

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)] is a novel neurokinin-1 receptor antagonist being developed for the prevention of chemotherapy-induced and postoperative nausea and vomiting. The disposition of [(14)C]casopitant was determined in a single-sequence study in six healthy male subjects after single-dose 90-mg i.v. and 150-mg oral administration. Blood, urine, and feces were collected at frequent intervals after dosing. Plasma, urine, and fecal samples were analyzed by high-performance liquid chromatography/mass spectrometry coupled with off-line radiodetection for metabolite profiling. Moreover, urine was also analyzed with (1)H-NMR to further characterize metabolites. Plasma pharmacokinetic parameters for casopitant, a major metabolite (M13, coded as GSK525060), and total radioactivity were determined. Absorption of radioactivity after oral administration appeared to be nearly complete; elimination was principally via the feces both after oral and intravenous administration. Urinary elimination accounted for only <8% of total radioactivity. The main circulating metabolites were a hydroxylated derivative, M13 (coded as GSK525060), and, after oral administration, a deacetylated and oxidized metabolite, M12 (coded as GSK631832). In addition, many other metabolites were identified in plasma and excreta: the principal route of metabolism included multiple oxidations, loss of the N-acetyl group, modifications or loss of the piperazine group, and cleavage of the molecule. Casopitant was extensively metabolized, and only negligible amounts were excreted as unchanged compound. Some phase II metabolites were also observed, particularly in urine.