Pharmacokinetics and brain penetration of casopitant, a potent and selective neurokinin-1 receptor antagonist, in the ferret

Drug Metab Dispos. 2008 Sep;36(9):1846-52. doi: 10.1124/dmd.108.021758. Epub 2008 Jun 12.


The pharmacokinetics and brain penetration of the novel neurokinin (NK)-1 receptor antagonist 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] were examined in ferrets. The ferret is known to respond to the full spectrum of agents recognized to induce emesis in humans, and the cisplatin-induced emesis models in the ferret have been used to establish the antiemetic potential of casopitant. Following single i.p. dosing to the ferret, casopitant was rapidly absorbed, with plasma and brain concentrations being approximately equal at 2 h postdose. The predominant radioactive component present in the ferret brain after a single dose of [(14)C]casopitant was parent compound, accounting for approximately 76% of the radioactivity. The major metabolites present in brain tissue following administration of [(14)C]casopitant were hydroxylated casopitant (M1) and the corresponding ketone product of the M1 metabolite (M2), which accounted for approximately 19 and 3% of the radioactivity in the brain extracts, respectively. All three molecules had relatively similar potency against ferret brain cortical NK-1, suggesting that the pharmacologic activity of casopitant in the ferret is largely attributable to parent compound and, to a lesser extent, to its oxidative metabolites. Because casopitant is intended to be administered in combination with ondansetron and because therapeutic synergy has been observed with this combination in the ferret, a drug interaction study was conducted. The additional pharmacodynamic benefit of the combination dose was not because of an alteration in the pharmacokinetics of either agent but is likely the result of the complementary mechanisms of pharmacologic action of the two drugs.

MeSH terms

  • Animals
  • Area Under Curve
  • Biotransformation
  • Brain / metabolism*
  • Chromatography, High Pressure Liquid
  • Chromatography, Thin Layer
  • Ferrets
  • Male
  • Neurokinin-1 Receptor Antagonists*
  • Piperazines / metabolism
  • Piperazines / pharmacokinetics*
  • Piperazines / pharmacology
  • Piperidines / metabolism
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology
  • Tandem Mass Spectrometry


  • Neurokinin-1 Receptor Antagonists
  • Piperazines
  • Piperidines
  • casopitant