Imidafenacin, a potent and selective antagonist of the M1 and M3-muscarinic receptor subtypes, is safe, efficacious, and tolerable for controlling the symptoms of overactive bladder (OAB). However, the precise mechanisms responsible for the bladder-selective pharmacological effects of this agent remain unclear. The basis of in vivo pharmacology is that antagonistic effects result from the occupancy of receptors, which may be examined using an in vivo radioligand binding assay. To characterize the in vivo muscarinic receptor binding of the highly specific activity of a new tritium-labeled imidafenacin ([3H]imidafenacin) in the bladder and other tissues of mice, and to clarify the mechanisms underlying the selective binding of bladder muscarinic receptors by imidafenacin. Measurements of total radioactivity and the in vivo muscarinic receptor binding of [3H]imidafenacin in the bladder and other tissues of mice after an intravenous injection of the radioligand were performed using a radioligand binding assay. The intravenous injection of [3H]imidafenacin exerted significantly longer-lasting binding of muscarinic receptors in the bladder than in other tissues in mice, and this in vivo muscarinic receptor binding of [3H]imidafenacin was markedly suppressed in the bladder only by the bilateral ligation of ureters. The concentration of [3H]imidafenacin was markedly higher in the urine than in the plasma of [3H]imidafenacin-injected mice. Imidafenacin excreted in the urine may significantly contribute to the selective and long-lasting binding of bladder muscarinic receptors. This result suggests the clinical significance of the efficacy and safety of antimuscarinic agents used to treat OAB. The pharmacological effects of antimuscarinic agents used commonly to treat OAB may be partially caused by the parent compounds or their active metabolites excreted in the urine. So, their efficacy and safety may be associated partly to the life-style such as the intake volume of water.
The Journal of pharmacology and experimental therapeutics. 2016 Nov 09 [Epub ahead of print]
Yoshihiko Ito, Shiori Kuraoka, Soma Endo, Ayaka Takahashi, Satomi Onoue, Shizuo Yamada
Univ of Shizuoka., Univ of Shizuoka .