title: The metabolic disposition of aprepitant, a substance P receptor antagonist, in rats and dogs.
abstract: The absorption, metabolism, and excretion of [14C]aprepitant, a potent and selective human substance P receptor antagonist for the treatment of chemotherapy-induced nausea and vomiting, was evaluated in rats and dogs. Aprepitant was metabolized extensively and no parent drug was detected in the urine of either species. The elimination of drug-related radioactivity, after i.v. or p.o. administration of [14C]aprepitant, was mainly via biliary excretion in rats and by way of both biliary and urinary excretion in dogs. Aprepitant was the major component in the plasma at the early time points (up to 8 h), and plasma metabolite profiles of aprepitant were qualitatively similar in rats and dogs. Several oxidative metabolites of aprepitant, derived from N-dealkylation, oxidation, and opening of the morpholine ring, were detected in the plasma. Glucuronidation represented an important pathway in the metabolism and excretion of aprepitant in rats and dogs. An acid-labile glucuronide of [14C]aprepitant accounted for approximately 18% of the oral dose in rat bile. The instability of this glucuronide, coupled with its presence in bile but absence in feces, suggested the potential for enterohepatic circulation of aprepitant via this conjugate. In dogs, the glucuronide of [14C]aprepitant, together with four glucuronides derived from phase I metabolites, were present as major metabolites in the bile, accounting collectively for approximately 14% of the radioactive dose over a 4- to 24-h period after i.v. dosing. Two very polar carboxylic acids, namely, 4-fluoro-alpha-hydroxybenzeneacetic acid and 4-fluoro-alpha-oxobenzeneacetic acid, were the predominant drug-related entities in rat and dog urine.
authors.affiliation: Dept of Drug Metabolism, Merck Research Laboratories, 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: George A
authors.initials: GA
authors.lastname: Doss
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.forename: Reza
authors.initials: R
authors.lastname: Anari
authors.forename: Paul E
authors.initials: PE
authors.lastname: Finke
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
authors.forename: Minghua
authors.initials: M
authors.lastname: Zhang
authors.forename: Bonnie
authors.initials: B
authors.lastname: Wang
authors.forename: John R
authors.initials: JR
authors.lastname: Strauss
authors.forename: Paul K
authors.initials: PK
authors.lastname: Cunningham
authors.forename: William P
authors.initials: WP
authors.lastname: Feeney
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Franklin
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Baillie
authors.forename: Shuet-Hing L
authors.initials: SH
authors.lastname: Chiu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000932:Antiemetics / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000077608:Aprepitant; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004285:Dogs; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000097:blood / Q000652:urine; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008333:Mandelic Acids / Q000097:blood / Q000652:urine; D013058:Mass Spectrometry; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D064729:Neurokinin-1 Receptor Antagonists; D010648:Phenylacetates / Q000097:blood / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: C483034:4-fluoro-alpha-oxobenzeneacetic acid; D000932:Antiemetics; D020719:Glucuronides; D008333:Mandelic Acids; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010648:Phenylacetates; D000077608:Aprepitant; C483033:4-fluoro-alpha-hydroxybenzeneacetic acid