In vivo bladder selectivity of imidafenacin, a novel antimuscarinic agent, assessed by using an effectiveness index for bladder capacity in rats

Abstract

Imidafenacin (KRP-197) is a novel antimuscarinic agent for overactive bladder treatment. The inhibitory effect of imidafenacin on detrusor contraction has been adopted for assessing their bladder selectivity, but this is becoming less convincing as an effectiveness index. We, therefore, reevaluated the bladder selectivity of imidafenacin and other antimuscarinics using their effects on the bladder capacity as an effectiveness index. Bladder capacity was measured by intermittent cystometry in urethane-anesthetized rats. In the tissues related to antimuscarinic side effects, the inhibitory actions were measured each on salivary secretion by electrical stimulation of chorda tympani, on rhythmical contractions in colon, and on carbamylcholine-induced bradycardia. Imidafenacin, solifenacin succinate, tolterodine tartrate, and propiverine hydrochloride significantly increased the bladder capacity, with minimum effective doses of 0.003, 1, 0.03, and 3 mg/kg (i.v.), respectively. The antimuscarinics tested, except for propiverine hydrochloride, shared a common property of increasing bladder capacity at a dose which did not affect micturition pressure. The relative bladder selectivity of imidafenacin, solifenacin succinate, and tolterodine tartrate was 15-, 1.7-, and 2.5-fold higher over salivary gland; 150-, 1.9-, and 9.2-fold higher over colon; and 50-, 12-, and 4.6-fold higher over heart, respectively, than that of propiverine hydrochloride. Thus, imidafenacin shows the most highly selective for bladder over the tissues related to major antimuscarinic side effects, compared to the other three well-known antimuscarinics tested in the rat.

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

“…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. Pharmacokinetic data have demonstrated that imidafenacin administered orally distributes predominantly to the bladder and exerts a more selective and longer-lasting effect on the bladder than on other tissues such as the submaxillary gland, colon, and brain 14.…”

Clinical Efficacy and Safety of Imidafenacin as Add-on Treatment for Persistent Overactive Bladder Symptoms Despite α-Blocker Treatment in Patients With BPH: The ADDITION STUDY

“…Imidafenacin did not cause urinary retention at the dose of 0.2 mg/day, probably because it has a shorter half-life (2.9 hours) and lower accumulation than other anticholinergic drugs. The second possibility is that imidafenacin is less likely to cause urinary retention or to increase the PVR because it may act more specifically on bladder afferent pathways, 27,28 in contrast to drugs acting on the detrusor muscle, which is involved in urinary retention and related to an increase in the PVR.…”

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

“…For example, there is an interaction between muscarinic and β-adrenergic systems in the bladder (Witte et al 2011), which may be important pathophysiologically when acetylcholine is released non-neuronally during the storage phase but also therapeutically if a combination treatment of muscarinic antagonists and β-adrenergic agonists is being considered. In this regard, we are still trying to understand why some muscarinic antagonists exhibit a certain degree of bladder selectivity (Yamazaki et al 2011), and it is largely unknown whether a similar phenomenon exists for β 3 -adrenoceptor agonists. Moreover, it is well established that the function of the systemic renin-angiotensin system is in part regulated by β-adrenoceptors, in humans β 1 -adrenoceptors, but a local renin-angiotensin system also exists in the urogenital tract (Comiter 2012).…”