QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huskey, S.-E. W. Articles by Chiu, S.-H. L. Search for Related Content PubMed PubMed Citation Articles by Huskey, S.-E. W. Articles by Chiu, S.-H. L.

BRAIN PENETRATION OF APREPITANT, A SUBSTANCE P RECEPTOR ANTAGONIST, IN FERRETS

Departments of Drug Metabolism (S.-E.W.H., B.J.D., R.B., R.I.S., C.A.K., S.-H.L.C.), Comparative Medicine (D.F.H.), and Immunology and Rheumatology (G.G.C.), Merck Research Laboratories, Rahway, New Jersey; and Departments of Medicinal Chemistry (A.P.W.), and Pharmacology (F.D.T., W.R., R.H.), Merck Research Laboratories, Terlings Park, Essex, United Kingdom

The pharmacokinetics, metabolism, and brain penetration of the neurokinin 1 (NK₁) receptor antagonist (substance P receptor antagonist), aprepitant (MK-0869), were examined in ferrets. This species exhibits human-type NK₁receptor pharmacology and is of proven value in the identification of clinically useful drugs for the treatment of chemotherapy-induced nausea and vomiting in humans. After a single p.o. dose of aprepitant at 1 or 2 mg/kg, plasma levels of the compound were between 200 and 270 ng/ml, 24 h after dosing. In the brain cortex, concentrations of aprepitant reached between 80 and 150 ng/g of tissue 24 h after dosing. The predominant radioactive component present in the plasma and the brain of ferrets at 24 or 48 h after a single oral dose of [¹⁴C]aprepitant at 3 mg/kg was the parent compound itself. The slow plasma clearance of aprepitant (1.5 ml/min/kg) and its abundance in ferret brain were in accord with its efficacy in blocking the retching and vomiting at 24 and 48 h postdose when ferrets were challenged with the emetic anticancer drug, cisplatin. When aprepitant and some of its metabolites were assessed for their in vitro binding affinity to the human NK₁receptor, aprepitant demonstrated the highest affinity. Collectively, these data suggested that aprepitant, rather than its metabolites, was responsible, primarily, for the antiemetic activity of this compound in the male ferret.

This article has been cited by other articles:

				E. Minthorn, T. Mencken, A. G. King, A. Shu, D. Rominger, R. R. Gontarek, C. Han, R. Bambal, and C. B. Davis Pharmacokinetics and Brain Penetration of Casopitant, a Potent and Selective Neurokinin-1 Receptor Antagonist, in the Ferret Drug Metab. Dispos., September 1, 2008; 36(9): 1846 - 1852. [Abstract] [Full Text] [PDF]

				E. Lindstrom, B. von Mentzer, I. Pahlman, I. Ahlstedt, A. Uvebrant, E. Kristensson, R. Martinsson, A. Noven, J. de Verdier, and G. Vauquelin Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1286 - 1293. [Abstract] [Full Text] [PDF]