Establishment and Validation of a Rabbit Model for In Vivo Pharmacodynamic Screening of Tachykinin NK₂ Antagonists

抄録

We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK₂ receptor (NK₂-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 NK₂-R agonist, βAla⁸-neurokinin A(4-10) (βA-NKA), was monitored as a PD marker. The analgesic effects of NK₂-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 NK₂-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 (r² = 0.61). Furthermore, the minimum effective doses on the VMR and ID₅₀ values calculated in the PD model were highly correlated (r² = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK₂-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 NK₂-R with in vivo therapeutic efficacy.