Effects of Anticholinergic Drugs Used for the Therapy of Overactive Bladder on P-Glycoprotein Activity

Abstract

We evaluated the effects of anticholinergic drugs principally used for the therapy of overactive bladder (OAB) on the activity of P-glycoprotein, an efflux transport protein, in Caco-2 cells. The time-dependent changes in the fluorescence of residual rhodamine 123, a P-glycoprotein activity marker, in the apical region of Caco-2 cells were measured in the presence of anticholinergic drugs using time-lapse confocal laser scanning microscopy. The effect of anticholinergic drugs on human P-glycoprotein ATPase activity was also measured. The fluorescence of residual rhodamine 123 in untreated Caco-2 cells decreased over time. The gradual decrease in the fluorescence was significantly inhibited by treatment with cyclosporine A, darifenacin, and trospium. In contrast, oxybutynin, N-desethyl-oxybutynin (DEOB), propiverine, and its active metabolites (M-1, M-2), imidafenacin, solifenacin, or tolterodine had little effect on the efflux of rhodamine 123. P-Glycoprotein ATPase activity was increased by darifenacin. Darifenacin and trospium reduced the rhodamine 123 transfer across the apical cell membrane. These data suggest that darifenacin and trospium interact with P-glycoprotein. Additionally, darifenacin influenced P-glycoprotein ATPase activity. These results suggest that darifenacin may be a substrate of P-glycoprotein. This study is the first paper to test simultaneously the effects of 10 anticholinergic drugs used currently for the therapy of OAB, on the P-glycoprotein.

Characterizing the Access of Cholinergic Antagonists to Efferent Synapses in the Inner Ear

“…There are key differences in how aliphatic and aromatic compounds interact with lipid membranes as well as a variety of transporter and efflux mechanisms that might facilitate drug permeability ( Metzner et al, 2006 ; Geldenhuys et al, 2010 ; Lind et al, 2021 ). Whether some of these differences contribute to the entry or efflux of these cholinergic drugs in or out of the inner ear and brain remains to be determined, but some cholinergic drugs are substrates for choline transporter uptake and P -glycoprotein-mediated efflux which may heavily influence drug accumulation in a particular compartment ( Daneman et al, 2010 ; Geldenhuys et al, 2010 ; Wakuda et al, 2019 ).…”

The impact of pharmacotherapy on sexual function in female patients being treated for idiopathic overactive bladder: a systematic review

“…Anticholinergics are widely used for patients with idiopathic overactive bladder [8,9]. These medications work by competitively blocking the muscarinic receptors within the detrusor muscle of the bladder [8].…”

“…The most ubiquitous muscarinic receptors within the detrusor are the M2 and M3 receptors [10]. Commonly reported side effects of the class of medication include somnolence, cognitive decline, blurred vision, dry mouth, and constipation [9]. Interestingly, although both M2 and M3 receptors have been found via real-time PCR analysis of human vaginal muscularis tissue taken at the time of hysterectomy, the effect on female sexual function of these medications remains poorly reported [11].…”