title: Antiemetic effects of a potent and selective neurokinin-1 receptor antagonist, FK886, on cisplatin- and apomorphine-induced emesis in dogs.
abstract: The antiemetic properties of a novel neurokinin-1 (NK1) receptor antagonist, FK886 ([3,5-bis(trifluoromethyl)phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl]methanone dihydrochloride), were studied in dog models of cisplatin- and apomorphine-induced emesis. Intravenously administered FK886 (0.32-1 mg/kg) significantly inhibited cisplatin-induced acute emesis during the 5-h observation period. Nearly complete inhibition was observed at 1 mg/kg. At an equivalent dose range, orally administered FK886 also significantly inhibited emesis, indicating good oral absorption. Similarly, FK886 inhibited apomorphine-induced emetic responses effectively following both intravenous and oral administration. The effects were long lasting, with 1.6 mg/kg of FK886 completely blocking apomorphine-induced retching and vomiting after a 12-h pretreatment period. Furthermore, FK886 showed rapid onset of antiemetic activity after oral administration. At doses of 0.32 mg/kg or more, a pretreatment time of 0.5 h was sufficient for complete inhibition of apomorphine-induced emetic responses. This fast onset after oral administration was supported by pharmacokinetic data, which demonstrated plasma levels of FK886 after oral administration reached levels similar to those 30 min after intravenous administration. These results suggest that FK886 has excellent antiemetic properties in dogs, and that its rapid-onset and long-lasting properties might make it a promising antiemetic agent.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. takako.furukawa@astellas.com
authors.forename: Takako Yoshino
authors.initials: TY
authors.lastname: Furukawa
authors.forename: Hiroe
authors.initials: H
authors.lastname: Nakayama
authors.forename: Aya
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Imazumi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamakuni
authors.forename: Hajime
authors.initials: H
authors.lastname: Sogabe
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Koji
authors.initials: K
authors.lastname: Takeshita
authors.forename: Masahiko
authors.initials: M
authors.lastname: Matsuo
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Manda
authors.forename: Wataru
authors.initials: W
authors.lastname: Uchida
mesh_terms: D000818:Animals; D000932:Antiemetics / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001058:Apomorphine; D002945:Cisplatin; D004285:Dogs; D005260:Female; D008297:Male; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064729:Neurokinin-1 Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000932:Antiemetics; C581895:FK886; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D001058:Apomorphine; D002945:Cisplatin