Selective Binding of Bladder Muscarinic Receptors in Relation to the Pharmacokinetics of a Novel Antimuscarinic Agent, Imidafenacin, to Treat Overactive Bladder

Abstract

The binding of orally administered imidafenacin, used to treat overactive bladders, to muscarinic receptors in rat tissue was characterized based on pharmacokinetics. The binding in six tissues including bladder tissue was measured using [N-methyl-3 H] scopolamine methyl chloride ([ 3 H]NMS). Pharmacokinetic parameters were estimated from measurements of the concentration of imidafenacin in serum, the bladder, and the submaxillary gland by liquid chromatography-mass spectrometry/mass spectrometry. The receptor binding affinity of imidafenacin in vitro was significantly lower in the bladder than submaxillary gland or colon. The oral administration of imidafenacin (0.79, 1.57, and 6.26 mol/kg) was characterized by a more selective and longer-lasting binding to muscarinic receptors in the bladder than other tissues. Imidafenacin showed little binding to brain muscarinic receptors, consistent with its minor effect on the central nervous system. Pharmacokinetic data showed that orally administered imidafenacin was distributed at a higher concentration in the bladder than the serum or submaxillary gland of rats. After the intravesical instillation of imidafenacin, there was significant binding of muscarinic receptors in the bladder. Furthermore, a significant level of imidafenacin was detected in the urine of rats given a 1.57 mol/kg concentration of this agent. The present study demonstrated that imidafenacin administered orally distributes predominantly to the bladder and exerts more selective and longer-lasting effect on the bladder than other tissues, such as the submaxillary gland, colon, and brain. Furthermore, the imidafenacin excreted in urine may play an important role in pharmacokinetic and pharmacological selectivity.

Muscarinic Receptor Binding of the Novel Radioligand, [3H]Imidafenacin in the Human Bladder and Parotid Gland

“…Since imidafenacin exhibited greater selectivity for the M 3 than M 2 subtype in CHO-K1 cells expressing human muscarinic receptors (4), the high affinity of [ 3 H]imidafenacin for muscarinic receptors in the human parotid gland reflects M 3 -subtype selectivity. In vivo functional and ex vivo muscarinic receptor binding experiments in rats (5,6) and clinical studies in humans (9,10) showed that imidafenacin selected the bladder over the exocrine gland. These in vivo results appear to contradict the M 3 -subtype selectivity observed in vitro, but in vivo bladder selectivity has been mainly attributed to the pharmacokinetic property of this agent (6).…”

“…Yamada et al (6) and Seki et al (12) examined the competitive inhibitory effect of imidafenacin on [Nmethyl- 3 H]scopolamine methyl chloride (NMS) binding and revealed that it was a potent inhibitor of muscarinic receptor binding sites in rat and human bladders. Thus, investigating the direct binding properties of imidafenacin to bladder muscarinic receptors is of importance.…”

“…Further studies revealed that imidafenacin exhibited functional selectivity toward the bladder over the salivary gland and had a negligible pharmacological effect on the CNS even at high doses (5,6). Imidafenacin is known to be a well-tolerated agent in clinical settings and causes fewer adverse effects (7,8).…”

Experience with imidafenacin in the management of overactive bladder disorder

“…Imidafenacin is the most bladder-selective anticholinergic available: it antagonizes both the M3 and M1 receptor subtypes in vitro and in vivo [Kobayashi et al 2007a[Kobayashi et al , 2007bYamada et al 2011b]. Furthermore, preclinical research indicates that the duration of receptor binding of imidafenacin is longer in the bladder than in the salivary glands, heart, colon and brain [Kobayashi et al 2007a[Kobayashi et al , 2007bYamada et al 2011b].…”

“…Furthermore, preclinical research indicates that the duration of receptor binding of imidafenacin is longer in the bladder than in the salivary glands, heart, colon and brain [Kobayashi et al 2007a[Kobayashi et al , 2007bYamada et al 2011b]. …”