Characterization of Bladder Selectivity of Antimuscarinic Agents on the Basis ofIn VivoDrug-Receptor Binding

Abstract

The in vivo muscarinic receptor binding of antimuscarinic agents (oxybutynin, solifenacin, tolterodine, and imidafenacin) used to treat urinary dysfunction in patients with overactive bladder is reviewed. Transdermal administration of oxybutynin in rats leads to significant binding of muscarinic receptors in the bladder without long-term binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin shows significant and long-lasting binding to muscarinic receptors in mouse tissues expressing the M3 subtype. Oral tolterodine binds more selectively to muscarinic receptors in the bladder than in the submaxillary gland in mice. The muscarinic receptor binding of oral imidafenacin in rats is more selective and longer-lasting in the bladder than in other tissues such as the submaxillary gland, heart, colon, lung, and brain, suggesting preferential muscarinic receptor binding in the bladder. In vivo quantitative autoradiography with (+)N-[11C]methyl-3-piperidyl benzilate in rats shows significant occupancy of brain muscarinic receptors with the intravenous injection of oxybutynin, solifenacin, and tolterodine. The estimated in vivo selectivity in brain is significantly greater for solifenacin and tolterodine than for oxybutynin. Imidafenacin occupies few brain muscarinic receptors. Similar findings for oral oxybutynin were observed with positron emission tomography in conscious rhesus monkeys with a significant disturbance of short-term memory. The newer generation of antimuscarinic agents may be advantageous in terms of bladder selectivity after systemic administration.

Antimuscarinic Use in Females With Overactive Bladder Syndrome Increases the Risk of Depressive Disorder: A 3‐Year Follow‐up Study

“…Those associations between antimuscarinics for OAB and subsequent depressive disorder or adverse depressive events might be explained by the antimuscarinics’ pharmacological and chemical properties . According to the previous literature, it is well known that all subtypes of muscarinic receptors (M 1 –M 5 ) are widely expressed throughout the body and brain, including the hippocampus, amygdala, thalamus, and so forth . Even though we supposed that the antimuscarinics for OAB would selectively bind to muscarinic receptors that are located on the bladder detrusor muscle, some antimuscarinics for OAB with high lipophilicity, neutral polarity, or low molecular size still cross the blood–brain barrier and further affect neurotransmission in the brain .…”

“…The matched comparison cohort (n = 9760; 5 comparison subjects per OAB woman who received antimuscarinics) was selected from the remaining OAB women in the LHID2005 who did not receive antimuscarinics. In addition, this comparison cohort was identified by matching OAB women receiving antimuscarinics in terms of age group (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), 40-49, 50-59, 60-69, and ࣙ70 years) and year of the index date. For comparison subjects, the date of the first diagnosis of OAB was identified as the index date.…”

Muscarinic receptors mediate cold stress‐induced detrusor overactivity in type 2 diabetes mellitus rats

“…To overcome this problem, we used imidafenacin, because it has the highest urinary bladder selectivity when compared with other muscarinic receptor antagonists, including solifenacin, tolterodine and propiverine. [21][22][23][24] Therefore, the present study suggests that the muscarinic M3 receptors expressed within the detrusors are a key component of cold stress-induced detrusor overactivity in the rats with inherited diabetes mellitus and latent LUTS.…”

“…Our cold stress model imitates the micturition patterns of human physiological responses; however, the model has the disadvantage that the analysis of partial reactions and changes in various receptors, neurotransmitters and/or enzymes is limited because of systematic reactions of “whole body” cooling. To overcome this problem, we used imidafenacin, because it has the highest urinary bladder selectivity when compared with other muscarinic receptor antagonists, including solifenacin, tolterodine and propiverine . Therefore, the present study suggests that the muscarinic M 3 receptors expressed within the detrusors are a key component of cold stress‐induced detrusor overactivity in the rats with inherited diabetes mellitus and latent LUTS.…”

Bioanalytical method for quantification of Solifenacin in rat plasma by LC-MS/MS and its application to pharmacokinetic study

“…After oral administration of vesicare to healthy volunteers, peak plasma levels (C max ) of Solifenacin reached within 3 to 8 h after administration and at steady state ranged from 32.3 to 62.9 ng/mL for the 5 and 10 mg vesicare tablets, respectively. The terminal elimination halflife of Solifenacin (SF) is approximately 45 to 68 h. Solifenacin is approximately 98% (in vivo) bound to human plasma proteins, principally to alpha1-acid glycoprotein (Morales-Olivas and Estan 2010; Doroshyenko and Fuhr 2009;Hoffstetter and Leong 2009;Kuipers et al 2004;Leone Roberti Maggiore et al 2012;Uchida et al 2004;Yamada et al 2012;Maruyama et al 2008;Kuipers et al 2006;Callegari et al 2011).…”