title: Investigating detrusor muscle concentrations of oxybutynin after intravesical delivery in an ex vivo porcine model.
abstract: Intravesical oxybutynin is highly effective in the treatment of overactive bladder. Traditionally the mechanism of action was explained by antagonism of muscarinic receptors located in the detrusor, however evidence now suggests antimuscarinics may elicit their effect by modifying afferent pathways in the mucosal region. This study aimed to investigate the bladder wall distribution of oxybutynin in an ex vivo setting providing tissue - layer specific concentrations of drug achieved after intravesical delivery. Whole ex vivo porcine bladders were intravesically instilled with 0.167 mg mL(-1) oxybutynin solution. After 60 min, tissue samples were excised, serially sectioned parallel to the urothelial surface and extracted drug quantified. Drug distribution into the urothelium, lamina propria and detrusor was determined. Oxybutynin permeated into the bladder wall at a higher rate than other drugs previously investigated (apparent transurothelial Kp = 1.36 × 10(-5) cm s(-1) ). After 60 min intravesical instillation, concentrations achieved in the urothelium (298.69 μg g(-1) ) and lamina propria (43.65 μg g(-1) ) but not the detrusor (0.93 μg g(-1) ) were greater than reported IC50 values for oxybutynin. This work adds to the increasing body of evidence suggesting antimuscarinics elicit their effects via mechanisms other than direct inhibition of detrusor contraction.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Williams
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Kay M
authors.initials: KM
authors.lastname: Lee
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Allender
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Bowen
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Gumbleton
authors.affiliation: Department of Research and Development in Urology and Gynaecology, Boston Scientific, Marlborough, Massachusetts, 01752.
authors.forename: Tim
authors.initials: T
authors.lastname: Harrah
authors.affiliation: Department of Urology, University Hospital of Wales, Heath Park, Cardiff, UK.
authors.forename: Aditya
authors.initials: A
authors.lastname: Raja
authors.affiliation: Department of Urology, University Hospital of Wales, Heath Park, Cardiff, UK.
authors.forename: Hrishi B
authors.initials: HB
authors.lastname: Joshi
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D008333:Mandelic Acids / Q000008:administration & dosage* / Q000378:metabolism*; D009092:Mucous Membrane / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000378:metabolism; D009132:Muscles / Q000378:metabolism*; D013552:Swine; D001743:Urinary Bladder / Q000378:metabolism*; D053201:Urinary Bladder, Overactive / Q000378:metabolism*; D019459:Urothelium / Q000378:metabolism
chemical_list: D008333:Mandelic Acids; D018727:Muscarinic Antagonists; C005419:oxybutynin
keywords: HPLC (high performance liquid chromatography); in vitro models; passive diffusion/transport; permeability; targeted drug delivery