Antiemetic effect of a potent and selective neurokinin-1 receptor antagonist, FK886, on cisplatin-induced acute and delayed emesis in ferrets.
The antiemetic effect of a potent and selective 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), on cisplatin-induced acute and delayed emesis in ferrets was studied. Intravenous administration of FK886 dose-dependently inhibited cisplatin (10 mg/kg)-induced acute emesis with a minimum effective dose (MED) of 0.32 mg/kg. In the same study, oral FK886 administered 8 h prior to cisplatin also dose-dependently inhibited the acute emesis during the 4-h observation period with an MED of 3.2 mg/kg. Further, when given by repeated oral administration of ≥1.6 mg/kg at 12-h intervals, the first dose being administered 1 min before cisplatin, FK886 significantly decreased the number of emetic responses in cisplatin (5 mg/kg)-induced delayed emesis. In the same study, oral FK886 (3.2 mg/kg) repeatedly administrated at 12-h intervals, the first dose being administered 36 h post cisplatin, also significantly attenuated the delayed emesis. Pharmacokinetic data in ferrets showed that plasma FK886 reached a maximum concentration within 0.5 h of administration, suggesting rapid oral absorption. In addition, rapid brain penetration of FK886 was suggested by complete and near complete inhibition of GR73632- and copper sulfate-induced emesis, respectively, by low-dose intravenous FK886 administered shortly before the emetogens. These results suggest that FK886 is an orally available NK1 receptor antagonist which is effective against both the acute and delayed emesis induced by cisplatin. Because of its therapeutic efficacy on the delayed emesis and rapid brain distribution after oral administration, FK886 may have potential as an antiemetic agent that can be used for interventional treatment of chemotherapy-induced delayed emesis.
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc.
Takako Yoshino
TY
Furukawa
Hiroe
H
Nakayama
Katsunori
K
Imazumi
Hisashi
H
Yamakuni
Koji
K
Takeshita
Masahiko
M
Matsuo
Toshitaka
T
Manda
Wataru
W
Uchida
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D008297:Male; D009025:Morpholines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*
D000932:Antiemetics; D000970:Antineoplastic Agents; C581895:FK886; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D018040:Receptors, Neurokinin-1; D002945:Cisplatin