Pharmacological Effects of Imidafenacin (KRP-197/ONO-8025), a New Bladder Selective Anti-cholinergic Agent, in Rats

Abstract

Imidafenacin (CAS 170105-16-5, KRP-197, ONO-8025) has been developed for the treatment of overactive bladder as a new anti-cholinergic with high affinities for muscarinic acetylcholine M3 and M1 receptors. The pharmacological profiles of imidafenacin on the urinary bladder function by determining carbamylcholine (CCh)-induced decrease in bladder capacity and distention-induced rhythmic bladder contraction in conscious rats were investigated. In addition, effects of imidafenacin on CCh-induced salivary secretion and performance in the Morris water maze task in rats were investigated to evaluate side effects, such as dry mouth and cognitive dysfunction in the central nervous system (CNS). Imidafenacin prevented the CCh-induced decrease in bladder capacity dose-dependently with an ID50 of 0.055 mg/kg. On the distention-induced rhythmic bladder contraction, imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin showed inhibitory effects with ID30's of 0.17, 15, 3.0, 3.2 and 0.85 mg/kg, respectively. The rank order of inhibitory potency was: imidafenacin > darifenacin > tolterodine > or = oxybutynin > propiverine. Imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin showed inhibitory effects on the CCh-stimulated salivary secretion with ID50's of 1.5, 14, 15, 4.4 and 1.2 mg/kg, respectively. The rank order of inhibitory potency was: darifenacin > or = imidafenacin > oxybutynin > propiverine > or = tolterodine. Imidafenacin at the doses of 1 and 10 mg/ kg did not affect the escape latencies in the Morris water maze task compared with those in vehicle controls. Oxybutynin at the dose of 100 mg/kg induced a significant increase in the escape latencies, but propiverine at the dose of 100 mg/kg did not induce significant changes. These results suggest that imidafenacin inhibits urinary bladder contraction to a greater extent than the salivary secretion (compared with the M3 receptor selective antagonist, darifenacin, and the non-selective antagonists, propiverine, tolterodine and oxybutynin) or the CNS functions, such as performance in the Morris water maze task (compared with oxybutynin). In conclusion, imidafenacin has organ selectivity for the bladder over the salivary gland, without influence on the central nervous system such as spatial learning and memory.

Characterization of Bladder Selectivity of Antimuscarinic Agents on the Basis ofIn VivoDrug-Receptor Binding

“…Imidafenacin also occupied muscarinic receptors to some extent, but did not induce cognitive impairment at all. This is consistent with pharmacological data showing that imidafenacin does not affect escape latency in the Morris water maze task in rats (spatial learning and memory) [65] and with clinical data showing that this agent is well-tolerated with fewer adverse effects [66-69]. Both imidafenacin and darifenacin have moderate polarity and low lipophilicity, suggestive of lower permeability.…”

Long-term safety, efficacy, and tolerability of imidafenacin in the treatment of overactive bladder: a review of the Japanese literature

“…In vitro research has shown that imidafenacin inhibits rat and human urinary bladder smooth muscle contraction by mediating antagonism of the M 3 muscarinic receptor subtype and regulating acetylcholine release by mediating the prejunctional facilitatory M 1 subtype 8,12. In addition, because imidafenacin has the highest relative potency (8.8), calculated as the ID 50 of salivary secretion divided by the ID 30 of distention-induced rhythmic bladder contraction in conscious rats, among propiverine (0.9), tolterodine (5.0), oxybutynin (1.4), and darifenacin (1.4), the drug has organ selectivity for the bladder over the salivary gland 9. Yamazaki et al reported that the relative bladder selectivity of imidafenacin, solifenacin, and tolterodine was 15-fold, 1.7-fold, and, 2.5-fold higher than for the salivary gland; 150-fold, 1.9-fold, and 9.2-fold higher than for the colon; and 50-fold, 12-fold, and 4.6-fold higher than for the heart, respectively, compared with propiverine in a rat study 13.…”

“…Imidafenacin, which was developed by Kyorin Pharmaceutical Company (Tokyo, Japan) is an antimuscarinic agent used to treat OAB and has high affinity for the M 3 and M 1 muscarinic receptor subtypes and low affinity for the M 2 subtype 8,9. In addition, it shows organ selectivity for the bladder over the salivary glands.…”

Effect of Imidafenacin on Nocturia and Sleep Disorder in Patients with Overactive Bladder

“…It has selectivity for M3 and M1 receptors over M2 receptor and apparent functional selectivity for the bladder [10]. In a phase 3 trial in Japan [11], the efficacy and tolerability of imidafenacin (0.1 mg twice daily) was compared to placebo and propiverine (20 mg once daily) in 781 patients with OAB.…”