title: Brain penetration of aprepitant, a substance P receptor antagonist, in ferrets.
abstract: 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 approximately 200 and 270 ng/ml, 24 h after dosing. In the brain cortex, concentrations of aprepitant reached between approximately 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 ( approximately 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.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. su_huskey@merck.com
authors.forename: Su-Er W
authors.initials: SE
authors.lastname: Huskey
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Dean
authors.forename: Ray
authors.initials: R
authors.lastname: Bakhtiar
authors.forename: Rosa I
authors.initials: RI
authors.lastname: Sanchez
authors.forename: F David
authors.initials: FD
authors.lastname: Tattersall
authors.forename: Wayne
authors.initials: W
authors.lastname: Rycroft
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.forename: Alan P
authors.initials: AP
authors.lastname: Watt
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: Carolann
authors.initials: C
authors.lastname: Keohane
authors.forename: Donald F
authors.initials: DF
authors.lastname: Hora
authors.forename: Shuet-Hing L
authors.initials: SH
authors.lastname: Chiu
mesh_terms: D000818:Animals; D000077608:Aprepitant; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003001:Cloning, Molecular; D006224:Cricetinae; D005289:Ferrets; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics*; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000235:genetics; D012588:Scintillation Counting; D013379:Substrate Specificity
chemical_list: D002250:Carbon Radioisotopes; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant