RT Journal Article
SR Electronic
T1 BRAIN PENETRATION OF APREPITANT, A SUBSTANCE P RECEPTOR ANTAGONIST, IN FERRETS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 785
OP 791
DO 10.1124/dmd.31.6.785
VO 31
IS 6
A1 Su-Er W. Huskey
A1 Brian J. Dean
A1 Ray Bakhtiar
A1 Rosa I. Sanchez
A1 F. David Tattersall
A1 Wayne Rycroft
A1 Richard Hargreaves
A1 Alan P. Watt
A1 Gary G. Chicchi
A1 Carolann Keohane
A1 Donald F. Hora
A1 Shuet-Hing L. Chiu
YR 2003
UL http://dmd.aspetjournals.org/content/31/6/785.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics