title: 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.
authors.affiliation: Development Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Nogi, Shimotsuga-gun, Tochigi, Japan. takanobu.yamazaki@mb.kyorin-pharm.co.jp
authors.forename: Takanobu
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Muraki
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Anraku
mesh_terms: D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012463:Saliva / Q000378:metabolism; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000188:drug therapy
chemical_list: D007093:Imidazoles; D018727:Muscarinic Antagonists; C120953:imidafenacin