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 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. Keywords:: NK2-receptor antagonist, colonic contraction, pharmacodynamic (PD) marker, pharmacokinetic (PK) / pharmacodynamic (PD), colorectal distension