title: Establishment and validation of a rabbit model for in vivo pharmacodynamic screening of tachykinin NK2 antagonists.
abstract: We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK(2) receptor (NK(2)-R) antagonists using pharmacological and pharmacokinetic (PK)/PD analyses. Under urethane anesthesia, changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective NK(2)-R agonist, βAla(8)-neurokinin A(4-10) (βA-NKA), was monitored as a PD marker. The analgesic effects of NK(2)-R antagonists were evaluated by monitoring visceromotor response (VMR) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. Intravenous administration of βA-NKA induced transient colonic contractions dose-dependently, which were inhibited by the selective NK(2)-R antagonists in dose- and/or plasma concentration-dependent manners. The correlation between PD inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r(2) = 0.61). Furthermore, the minimum effective doses on the VMR and ID(50) values calculated in the PD model were highly correlated (r(2) = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK(2)-R antagonists. In a drug discovery process, this PD model could enhance the therapeutic candidate selection for irritable bowel syndrome, pharmacologically connecting in vitro affinity for NK(2)-R with in vivo therapeutic efficacy.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Shiho
authors.initials: S
authors.lastname: Matsumoto-Okano
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Inatomi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujioka
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kamiguchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Akio
authors.initials: A
authors.lastname: Imanishi
authors.forename: Makiko
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Kasei
authors.initials: K
authors.lastname: Miura
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsukimi
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods* / Q000592:standards*; D008297:Male; D023421:Models, Animal; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D001549:Benzamides; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C073839:SR 48968