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-3H] scopolamine methyl chloride ([3H]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 μmol/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 μmol/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.
An overactive bladder is characterized by an increased frequency of micturition, urgency, and urge incontinence. The condition has a detrimental effect on physiological functioning and psychological well being as well as significantly decreasing quality of life (Bulmer and Abrams, 2000). Antimuscarinic agents are used widely to treat overactive bladder because parasympathetic innervation is the predominant stimulus for bladder contraction (Anderson, 1993; Abrams and Andersson, 2007). Although effective, their use is associated with anticholinergic side effects, such as dry mouth, constipation, somnolence, blurred vision, and central nervous system (CNS) dysfunction including cognitive impairment. Dry mouth is the most common side effect and reduces quality of life. Therefore, numerous studies of antimuscarinic agents have focused on selectivity for the urinary bladder over the salivary gland. The incidence of side effects on the CNS is generally lower than that of dry mouth but is of great concern in elderly patients because the permeability of the blood-brain barrier increases with aging (Katz et al., 1998; Pakulski et al., 2000; Ouslander, 2004; Ancelin et al., 2006).
A novel antimuscarinic agent, imidafenacin, 4-(2-methyl 1-H-imidazol-1-yl)-2,2,diphenyl butanamide) (KRP-197/ONO-8025) (Fig. 1), is currently being developed for the treatment of overactive bladder in Japan. Imidafenacin is a well tolerated agent with fewer adverse effects (Homma and Yamaguchi, 2008; Homma et al., 2008, 2009; Ohno et al., 2008). It has been reported to have high affinity for M3 receptors, which play an important role in bladder contraction, to exhibit functional selectivity toward the bladder over the salivary gland and to have little pharmacological effect on the CNS even at high doses (Kobayashi et al., 2007a,b). Murakami et al. (2003) showed that imidafenacin exerted an inhibitory effect on postjunctional muscarinic receptors as well as prejunctional muscarinic receptors to modulate the release of acetylcholine in human detrusor smooth muscles. Thus, imidafenacin may select the bladder over the salivary gland, reducing the risk of side effects on the CNS in the treatment of overactive bladders.
We previously stressed the importance of characterizing the binding of ligands to receptors under the influence of various pharmacokinetic and pharmacodynamic factors (Yamada et al., 2003; Oki et al., 2004, 2005, 2006; Maruyama et al., 2008; Yoshida et al., 2010a). The present study was undertaken to examine the bladder-selectivity of imidafenacin based on the binding of muscarinic receptors in rats. We characterized the binding properties of orally administered imidafenacin in the rat bladder, submaxillary gland, heart, colon, lung, and brain, compared with those of oxybutynin and evaluated the pharmacokinetic properties of imidafenacin. We also conducted intravesical instillation to clarify the receptor binding activity of urinary imidafenacin.
Materials and Methods
[N-methyl-3H]Scopolamine methyl chloride ([3H]NMS, 2.59–2.65 TBq/mmol) was purchased from PerkinElmer Life Sciences and Analytical Sciences (Waltham, MA). Imidafenacin was donated by Kyorin Pharmaceutical Co., Ltd. (Tokyo, Japan). Oxybutynin hydrochloride (oxybutynin) was purchased from Sigma-Aldrich (St. Louis, MO). All other chemicals were obtained from commercial sources. Imidafenacin was dissolved in distilled water containing hydrochloric acid and adjusted to pH 7 with a sodium hydroxide solution. Oxybutynin was dissolved in distilled water. Each solution was diluted with 30 mM Na+/HEPES buffer, pH 7.5, in the in vitro experiments and diluted with saline in the intravesical instillation experiments.
Male Sprague-Dawley rats (250–300 g) 8 to 10 weeks of age were purchased from Japan SLC (Shizuoka, Japan). They were housed in the laboratory with free access to food and water and maintained on a 12-h light/dark cycle in a room with controlled temperature (24 ± 2°C). Animal care and experiments were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of the University of Shizuoka.
Administration of Imidafenacin and Oxybutynin.
For the oral administration of imidafenacin and oxybutynin, rats were fasted for 16 h and then given oral imidafenacin (0.79–6.26 μmol/kg) suspended in a 0.3% carboxymethylcellulose solution or oxybutynin (76.1 μmol/kg) dissolved in distilled water. Their doses were pharmacologically relevant (Kobayashi et al., 2007a,b; Oki et al., 2006). Control animals received the vehicle alone. For the intravesical instillation of imidafenacin, fasted rats were anesthetized with diethyl ether, and their bladder was exposed. A 27-gauge needle connected to a syringe was inserted into the bladder through the bladder dome, and imidafenacin (30–3000 nM/0.2 ml per rat) was directly instilled in the bladder for 30 min. Control animals received saline alone.
At various points in time (oral, 1–12 h; intravesical, 0.5 h) after the drug administration, rats were killed by taking blood from the descending aorta under anesthesia with diethyl ether. The bladder, submaxillary gland, heart, colon, lung, and brain were then dissected, and fat and blood vessels were removed by trimming. The tissues were minced with scissors and homogenized in a Kinematica Polytron homogenizer (Kinematica, Littau-Lucerne, Switzerland) in 19 volumes of ice-cold 30 mM Na+/HEPES buffer, pH 7.5. The homogenate was centrifuged at 40,000g for 20 min. The pellet was suspended in buffer for the binding assay. In the ex vivo experiment, there was a possibility that imidafenacin and oxybutynin might dissociate in part from the receptor sites during the tissue preparation (homogenization and suspension) process after the drug administration. Our group has shown previously that the dissociation of antagonists from receptor sites at 4°C was extremely slow (Yamada et al., 1980). Therefore, to minimize the dissociation of imidafenacin and oxybutynin from the receptor sites, all steps were performed at 4°C. Protein concentrations were measured by the method of Lowry et al. (1951).
Muscarinic Receptor Binding Assay.
The binding assay for muscarinic receptors was performed using [3H]NMS as described previously (Oki et al., 2004). The homogenates (100–900 μg of protein) of rat tissues were incubated with different concentrations (0.06–1.0 nM) of [3H]NMS in 30 mM Na+/HEPES buffer, pH 7.5. Incubation was carried out for 60 min at 25°C. The reaction was terminated by rapid filtration (Cell Harvester; Brandel Co., Gaithersburg, MD) through Whatman GF/B glass fiber filters (Whatman, Clifton, NJ), and the filters were then rinsed three times with 3 ml of ice-cold buffer. Tissue-bound radioactivity was extracted from the filters overnight by immersion in scintillation fluid [2 liters of toluene, 1 liters of Triton X-100, 15 g of 2,5-diphenyloxazole, and 0.3 g of 1,4-bis[2-(5-phenyloxazolyl)]benzene] and measured with a liquid scintillation counter. Specific [3H]NMS binding was determined experimentally from the difference between counts in the absence and presence of 1 μM atropine. All assays were conducted in duplicate.
Measurement of Imidafenacin in Serum and Tissues.
At various time points (1–12 h) after the oral administration of imidafenacin (1.57 and 6.26 μmol/kg), rats were killed by taking blood from the descending aorta under anesthesia with diethyl ether. The bladder and submaxillary gland were dissected, and fat and blood vessels were removed by trimming. Serum samples were isolated from whole blood by centrifugation. The serum, bladder, and submaxillary gland were stored at −30°C until concentrations of imidafenacin were determined. For the measurement of urinary imidafenacin levels, rats were anesthetized with isoflurane, and a catheter was inserted into the top of the bladder for the collection of urine. A catheter was also inserted into the stomach for the drug administration. The urine from conscious rats fixed in the Bollman cage was collected 0 to 6 h after the intragastric administration of imidafenacin (1.57 μmol/kg).
The concentrations of imidafenacin in the serum, urine, bladder, submaxillary gland, and colon of rats were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS) (API 5000; Applied Biosystems/MDS Sciex, Foster City, CA) as described previously (Masuda et al., 2007). Serum and urine samples (100 μl) containing internal standards were applied to C18 solid-phase extraction columns, which had first been conditioned with 1 ml of methanol and 1 ml of water. After adsorption of the samples, cartridges were washed with 1 ml of water. Analytes were then eluted with 1 ml of methanol, evaporated dry under a stream of nitrogen, and reconstituted in 100 μl of mobile phase [0.1% formic acid/acetonitrile, 77/23 (v/v)]. Furthermore, reconstituted samples were filtrated by centrifuging at 3000 rpm for 10 min at 4°C, and the filtrates (5 μl) were injected into the LC-MS/MS system for quantification.
The bladder, submaxillary gland, and colon were dissolved with 24 volumes of 1 M sodium hydroxide solution at 50°C for 1 h in a water bath. These solutions were shaken with chloroform (6 ml) and centrifuged at 3000 rpm for 10 min at 4°C. The organic phase was transferred to another tube and evaporated dry under a stream of nitrogen. The residues were reconstituted in 100 μl of mobile phase [0.1% formic acid/acetonitrile, 75/25 (v/v)]. Reconstituted samples were filtrated by centrifuging at 3000 rpm for 10 min at 4°C, and filtrates (5 μl) were injected into the LC-MS/MS system for quantification. Protonated molecules were used as precursor ions with monitoring of the following transitions for imidafenacin and the internal standard, respectively: m/z 320 > 238 and m/z 334 > 238. The limit of quantification for imidafenacin was 0.06 pmol/ml.
The [3H]NMS binding data were subjected to a nonlinear regression analysis using Prism software (version 4; GraphPad Software, Inc., San Diego, CA). The apparent dissociation constant (Kd) and maximal number of binding sites (Bmax) for [3H]NMS were estimated. The ability of imidafenacin and oxybutynin to inhibit specific [3H]NMS binding (250 pM) was estimated from the IC50, which is the molar concentration of antimuscarinic agents necessary to displace 50% of specific [3H]NMS binding. The inhibition constant Ki was calculated from the equation Ki = IC50/(1 + L/Kd), where L represents the concentration of [3H]NMS.
Pharmacokinetic analyses of imidafenacin in the serum, bladder, and submaxillary gland were calculated by the noncompartment method. The maximal concentration (Cmax) of imidafenacin in the serum, bladder, and submaxillary gland was obtained directly from the original data. The elimination rate constant (kel) was determined by GraphPad Prism. The elimination half-life (t1/2) was calculated as ln2 divided by kel. The area under the imidafenacin concentration-time curve and area under the moment curve from time 0 to the time of the last measurable concentration (AUCt and AUMCt) were calculated using the linear trapezoidal rule, and the AUC∞ and AUMC∞ by dividing the last measurable concentration by kel. Total clearance (Cltot/F) was calculated by using AUC∞ and applied dose (D), where F is the bioavailability of imidafenacin. The steady-state volume of distribution (Vss/F) was calculated by using D, AUC∞, and AUMC∞.
The statistical analysis of the receptor binding data were performed with Student's t test and a one-way analysis of variance, followed by Dunnett's test for multiple comparisons. All data are expressed as the mean ± S.E. Statistical significance was accepted at P < 0.05.
Inhibitory Effect of Imidafenacin on Specific [3H]NMS Binding in Rat Tissues In Vitro.
Imidafenacin (0.3–100 nM) and oxybutynin (1–100 nM) inhibited specific [3H]NMS binding in the bladder, submaxillary gland, heart, colon, lung, and brain of rats in a concentration-dependent manner (Fig. 2). The respective Ki and Hill coefficient values are listed in Table 1. The Ki values were lowest in the submaxillary gland and colon, followed by the brain, lung, bladder, and heart. In fact, the Ki value for imidafenacin in the bladder was significantly larger than that in the submaxillary gland (4-fold) and colon (2.4-fold) and significantly (1/2.4) smaller than that in the heart. The Ki values for the lung and brain were similar to that in the bladder. Likewise, the Ki value for oxybutynin in the bladder was significantly (1.8-fold) larger than that in the submaxillary gland and smaller than that in the heart. The Ki values for oxybutynin in the submaxillary gland and brain were slightly but significantly (3.3- and 1.6-fold, respectively) larger than the values for imidafenacin. The Hill coefficients for imidafenacin and oxybutynin in rat tissues were close to unity, with the exception of that for imidafenacin in the lung, which was 0.70.
Effect of Oral Administration of Imidafenacin on Muscarinic Receptors in Rat Tissues.
The oral administration of imidafenacin (1.57 μmol/kg) significantly increased Kd values for specific [3H]NMS binding in the bladder and submaxillary gland compared with the corresponding control values (Table 2). These effects were slight but statistically significant in the bladder (13–27%) at 1 to 6 h and in the submaxillary gland (37 and 32%) at 1 and 3 h. The Kd values in the heart, colon, lung, and brain were not significantly different from control values at 1 to 9 h. Likewise, the lower dose (0.79 μmol/kg) of this agent exerted a significant enhancement of Kd values for [3H]NMS at 1 (15%) and 3 (14%) h later in the bladder and at 1 h (18%) in the submaxillary gland (data not shown).
Furthermore, the oral administration of imidafenacin at a 4-fold larger dose (6.26 μmol/kg) increased Kd values for specific [3H]NMS binding in the bladder, submaxillary gland, heart, colon, and lung compared with the corresponding control values (Table 3), with the increase being significant in the bladder (22–32%) at 1 to 9 h and in the submaxillary gland (59 and 97%), heart (19 and 18%), colon (70 and 74%), and lung (44% and 64%) at 1 and 3 h. Imidafenacin had no effect on Bmax values in each tissue. The oral administration of imidafenacin even at 6.26 μmol/kg had no effect on Kd and Bmax values in the brain (Table 3).
The oral administration of oxybutynin (76.1 μmol/kg) increased Kd values in the bladder, submaxillary gland, heart, colon, lung, and brain. These effects were significant in the brain (48%) at 1 h, in the bladder (79 and 58%), submaxillary gland (188 and 179%), and colon (109 and 111%) at 1 and 3 h, and in the heart (38–66%) and lung (57–193%) at 1 to 6 h (Table 4). In addition, the oral administration of oxybutynin caused a significant and sustained (24–34%) reduction in Bmax values for specific [3H]NMS binding in the submaxillary gland from 1 to 12 h. Likewise, a significant (29 and 25%, respectively) decrease in the Bmax value was observed in the colon at 1 and 3 h.
Effect of Intravesical Administration of Imidafenacin on Muscarinic Receptors in Rat Tissues.
After the intravesical instillation of imidafenacin (30–3000 nM/0.2 ml per rat) for 30 min, there were significant dose-dependent increases in Kd values for specific [3H]NMS binding in the bladder compared with the control value (Table 5). The increases at 30, 300, and 3000 nM imidafenacin were 37, 43, and 62%, respectively. There was little change in Kd values in the submaxillary gland and heart and Bmax values in any tissue after the intravesical instillation of imidafenacin.
Pharmacokinetics of Imidafenacin.
Figure 3 shows the time course of the concentration of imidafenacin in the serum, bladder, and submaxillary gland of rats after the oral administration (1.57 and 6.26 μmol/kg). There were dose-dependent increases in the concentration in serum and tissues. The concentration of imidafenacin reached a maximum at 1 h in the serum and at 3 h in the bladder and submaxillary gland. Furthermore, the tissue concentrations (picomoles per gram of wet weight tissue, mean ± S.E.) of imidafenacin in the colon 3 h after the oral administration were 9.01 ± 1.64 (1.57 μmol/kg) (n = 4) and 11.6 ± 2.0 (6.26 μmol/kg) (n = 5). It is noteworthy that tissue concentrations were remarkably higher than the concentration in serum.
The pharmacokinetic parameters of imidafenacin were calculated from these concentration-time profiles (Table 6). The Cmax and AUC of the serum concentration and AUCtissue/AUCserum were significantly higher (67, 75, and 75%, respectively) in the bladder than submaxillary gland after the oral administration of imidafenacin (1.57 μmol/kg). There was also a significant difference in the Cmax and AUC between the bladder and submaxillary gland after oral treatment (6.26 μmol/kg). The rate of rise in the Cmax and AUC was significantly greater in the bladder (132 and 149%, respectively) than in the submaxillary gland. Furthermore, the AUCtissue/AUCserum was 148% greater in the bladder than in the submaxillary gland.
The concentration of imidafenacin in the urine of rats that received an intragastric administration of this agent was also measured. The urinary concentration was 231 and 191 nM, respectively, 0 to 3 and 3 to 6 h after the administration (1.57 μmol/kg).
Here, the effects of orally administered imidafenacin on the binding of muscarinic receptors in rat tissues was characterized in relation to the pharmacokinetics of drug. In the experiments in vitro, imidafenacin competed in a concentration-dependent manner with [3H]NMS for binding sites in the bladder, submaxillary gland, colon, lung, and brain, with a potency equal to or greater that of oxybutynin. In addition, the affinity of imidafenacin for muscarinic receptors was significantly lower in the bladder than submaxillary gland or colon, whereas it was significantly greater than that in the heart. Greater affinity of imidafenacin for muscarinic receptors in the exocrine gland than bladder was also observed in human tissues (Y. Ito, H. Ogoda, and S. Yamada, unpublished observations).
The heart and salivary gland predominantly contain M2 and M3 muscarinic receptors, respectively (Giraldo et al., 1988; Caulfield, 1993), whereas the bladder contains both subtypes, although M2 receptors dominate (Wang et al., 1995). Furthermore, our recent study with M1 to M5 receptors knockout mice has shown that the M3 subtype is expressed predominantly in the submaxillary gland and moderately in the bladder, whereas the M2 receptor is the major subtype in the bladder and heart (Ito et al., 2009). The normal physiological contraction of the bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role (Ruggieri and Braverman, 2006; Frazier et al., 2008). Because imidafenacin exhibited greater selectivity for the M3 than M2 subtype (Kobayashi et al., 2007a), the observed high affinity of this drug for muscarinic receptors in the rat submaxillary gland reflects M3 subtype selectivity (Table 1).
After the oral administration of imidafenacin (0.79–6.26 μmol/kg), there were dose- and time-dependent increases in Kd values for specific [3H]NMS binding in the bladder, submaxillary gland, heart, colon, and lung but not brain of rats compared with each control value. To the extent that an increase in Kd values for radioligands in drug-pretreated tissues in the radioreceptor assay refers generally to competition with the radioligand for same binding sites (Yamada et al., 2003; Oki et al., 2004, 2005, 2006; Yoshida et al., 2010a), these results strongly suggest that orally administered imidafenacin binds significantly to muscarinic receptors in rat tissues. The binding by imidafenacin at 0.79 and 1.57 μmol/kg was observed only in the bladder and submaxillary gland and was rapid in onset and relatively longer-lasting in the bladder as characterized by the increase in Kd values for [3H]NMS, which appeared at 1 h and lasted until at least 6 h (1.57 μmol/kg; Table 2). Furthermore, significant activity at a 4-fold dose (6.26 μmol/kg) of imidafenacin was observed in the bladder, submaxillary gland, heart, colon, and lung, and the binding was remarkably longer-lasting in the bladder than other tissues (Table 3). The results demonstrate that orally administered imidafenacin binds muscarinic receptors more selectively in the bladder than in other tissues.
There seems to be a significant difference between imidafenacin and oxybutynin in their binding characteristics ex vivo. In the case of oxybutynin, the increase in Kd for [3H]NMS in the bladder was observed only at 1 and 3 h after the oral administration, suggesting a transient binding of muscarinic receptors (Table 4). Similar or greater binding by oral oxybutynin was observed in the submaxillary gland, heart, colon, and lung. In addition, there was a significant decrease in the Bmax for [3H]NMS in the submaxillary gland and colon lasting at least 3 or 12 h. A similarly sustained reduction of [3H]NMS binding sites (Bmax) in the rat submaxillary gland after the oral administration of oxybutynin was reported by Oki et al. (2006). Such noncompetitive antagonism by oral oxybutynin may be responsible for the extremely long-lasting binding of muscarinic receptors in the submaxillary gland and colon. It is noteworthy that the sustained receptor binding activity in the submaxillary gland and colon seen after oral oxybutynin treatment was not observed after oral imidafenacin treatment.
Kobayashi et al. (2007a,b) have shown that the intragastric administration of imidafenacin at doses similar to those used in the current study exerted significantly more pronounced inhibitory effects on the rhythmic bladder contraction than on carbachol-induced salivation in rats. Thus, the functional selectivity of imidafenacin for the bladder versus salivary gland was verified directly based on assessments of the binding of muscarinic receptors in these tissues after the oral administration. In addition, our finding in rats may be of clinical relevance because the selectivity of imidafenacin toward muscarinic receptors in the bladder compared with the salivary gland was demonstrated via a clinical route of administration. Homma et al. (2009) showed that the incidence of adverse effects, such as dry mouth, an increase in the QT interval corrected for heart rate, and arrhythmia, was significantly lower with imidafenacin than with propiverine. Thus, imidafenacin was well tolerated for the treatment of an overactive bladder in Japanese patients (Homma and Yamaguchi, 2008; Homma et al., 2009; Ohno et al., 2008).
Short-term and chronic administration of oxybutynin in elderly subjects resulted in mild nondegenerative cognitive dysfunction (Katz et al., 1998; Ancelin et al., 2006). Significant occupancy of CNS muscarinic receptors by oxybutynin also was demonstrated by autoradiography ex vivo (Maruyama et al., 2008). It was shown that oral imidafenacin (0.79, 1.57, and 6.26 μmol/kg) had little effect on binding parameters in the rat brain, whereas oxybutynin bound significantly to muscarinic receptors. Our recent results with autoradiography and positron emission tomography have shown that intravenous injection of oxybutynin but not imidafenacin binds significantly to muscarinic receptors in the rat brain (Yoshida et al., 2010b). In agreement with these findings, imidafenacin at similar doses did not affect escape latency in the Morris water maze task, suggesting little effect on spatial learning and memory (Kobayashi et al., 2007b). Therefore, these behavioral observations may be based on little occupancy of brain muscarinic receptors possibly as a result of the low permeability of the blood-brain barrier.
The orally administered imidafenacin was distributed more to the bladder and submaxillary gland than the serum, and the tissue concentration was much higher in the bladder than the submaxillary gland (Fig. 3; Table 6). The imidafenacin concentration in the colon was markedly low. The specific distribution of imidafenacin to the bladder might be related to its significant excretion into the urine. Up to 48 h after the oral administration of imidafenacin (0.1 mg) in healthy volunteers, approximately 7.3% of the dose was excreted into urine as the parent compound, and the maximal concentration was 293 nM (Masuda et al., 2007). A similar concentration (approximately 200 nM) of imidafenacin was excreted in the urine of rats that received this agent at a dose of 1.57 μmol/kg. In fact, we observed significant binding of bladder muscarinic receptors after the intravesical instillation of imidafenacin at concentrations of 30 to 3000 nM (Table 5). Taken together, these results suggest that some imidafenacin is transferred directly from urine to the bladder tissue by simple diffusion; thus, this agent could contribute greatly to the selective and long-lasting binding of bladder muscarinic receptors in rats. Therefore, it can be presumed that the significant binding of bladder muscarinic receptors by the excreted urinary imidafenacin is relevant pharmacologically in terms of the functional blockade of these receptors.
In conclusion, the current study demonstrated that orally administered imidafenacin 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. Such selectivity may be attributable to a direct blockade of bladder muscarinic receptors by the excreted urinary imidafenacin. Thus, imidafenacin may be more efficacious than oxybutynin in treating patients with an overactive bladder.
Participated in research design: Yamada.
Conducted experiments: Ogoda, Seki, Fukata, Nakamura, and Ito.
Contributed new reagents or analytic tools: Fukata and Nakamura.
Performed data analysis: Ogoda, Seki, and Ito.
Wrote or contributed to the writing of the manuscript: Yamada, Ogoda, and Ito.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
- central nervous system
- N-methyl-scopolamine methyl chloride
- area under the time-concentration curve
- area under the moment curve
- liquid chromatography
- mass spectrometry
- 4-(2-methyl 1-H-imidazol-1-yl)-2,2,diphenyl butanamide.
- Received June 30, 2010.
- Accepted November 2, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics