Comparative Influence of Imidafenacin and Oxybutynin on Voiding Function in Rats with Functional Urethral Obstruction

Abstract

An antimuscarinic therapy may increase the risk of voiding dysfunction. However, it is unclear whether the relative risk of voiding dysfunction is different among antimuscarinics. Therefore we determined the potencies both in enhancing the bladder capacity (BC), effectiveness, and in decreasing the maximum urinary flow rate (Qmax), voiding dysfunction, to compare their therapeutic indices.

Under urethane anesthesia, urinary flow rate was measured at distal urethra using an ultrasonic flow meter in female Sprague-Dawley rats with functional urethral obstruction induced by a continuous i. v. infusion of α₁-adrenoceptor agonist A-61603 (0.03 μg/kg/min). In a separate group of urethane-anesthetized rats without urethral obstruction, an intermittent cystometry was performed to determine BC.

Intravenous imidafenacin and oxybutynin produced a significant dose-dependent decrease in Qmax with the minimum doses of 0.03 and 1 mg/kg, respectively. Imidafenacin and oxybutynin markedly increased BC, with minimum doses of 0.01 and 3 mg/kg, respectively. At the minimum dose to increase BC, oxybutynin caused a significant increase in residual urine volume with a significant decrease in voiding efficiency, whereas imidafenacin had no influence on these values. The relative influence index, which is the ratio of the minimum influence dose between in decreasing of Qmax and in increasing of BC, of imidafenacin was 10 fold higher than that of oxybutynin.

This study suggests that imidafenacin has a lower relative risk of voiding difficulty compared with oxybutynin in rats. These results provide new information that antimuscarinics may have varying degrees of impact on voiding difficulty.

Key words

overactive bladder - benign prostatic hyperplasia - imidafenacin - oxybutynin - urinary flow

• References

• 1 Athanasopoulos A, Giannitsas K. An overview of the clinical use of antimuscarinics in the treatment of overactive bladder. Advances in urology 2011;
• 2 Martín-Merino E, García-Rodríguez LA, Massó-González EL et al. Do oral antimuscarinic drugs carry an increased risk of acute urinary retention?. The Journal of urology 2009; 182: 1442-1448
• 3 Verhamme KMC, Sturkenboom MCJM, Stricker BHC et al. Drug-induced urinary retention: incidence, management and prevention. Drug safety 2008; 31: 373-388
• 4 Afonso ASM, Verhamme KMC, Stricker BHC et al. Inhaled anticholinergic drugs and risk of acute urinary retention. BJU international 2011; 107: 1265-1272
• 5 Loke YK, Singh S. Risk of acute urinary retention associated with inhaled anticholinergics in patients with chronic obstructive lung disease: systematic review. Therapeutic advances in drug safety 2013; 4: 19-26
• 6 Radomski SB. Update on medical therapy for male LUTS. Canadian Urological Association journal=Journal de l’Association des urologues du Canada 2014; 8: S148-S150
• 7 Hao N, Tian Y, Liu W et al. Antimuscarinics and α-blockers or α-blockers monotherapy on lower urinary tract symptoms – a meta-analysis. Urology 2014; 83: 556-562
• 8 Woderich R, Fowler CJ. Management of lower urinary tract symptoms in men with progressive neurological disease. Current opinion in urology 2006; 16: 30-36
• 9 Andersson K-E. Storage and voiding symptoms: pathophysiologic aspects. Urology 2003; 62: 3-10
• 10 Finney SM, Andersson K-E, Gillespie JI et al. Antimuscarinic drugs in detrusor overactivity and the overactive bladder syndrome: motor or sensory actions?. BJU international 2006; 98: 503-507
• 11 Yokoyama O, Tanaka I, Kusukawa N et al. Antimuscarinics suppress adenosine triphosphate and prostaglandin E2 release from urothelium with potential improvement in detrusor overactivity in rats with cerebral infarction. The Journal of urology 2011; 185: 2392-2397
• 12 Kobayashi F, Yageta Y, Segawa M et al. Effects of imidafenacin (KRP-197/ONO-8025), a new anti-cholinergic agent, on muscarinic acetylcholine receptors. High affinities for M3 and M1 receptor subtypes and selectivity for urinary bladder over salivary gland. Arzneimittel-Forschung 2007; 57: 92-100
• 13 Yamazaki T, Muraki Y, Anraku T. In vivo bladder selectivity of imidafenacin, a novel antimuscarinic agent, assessed by using an effectiveness index for bladder capacity in rats. Naunyn-Schmiedeberg’s archives of pharmacology 2011; 384: 319-329
• 14 Homma Y, Yamaguchi O. A randomized, double-blind, placebo- and propiverine-controlled trial of the novel antimuscarinic agent imidafenacin in Japanese patients with overactive bladder. International journal of urology 2009; 16: 499-506
• 15 Nishizawa O, Yamaguchi O, Takeda M et al. Randomized controlled trial to treat benign prostatic hyperplasia with overactive bladder using an alpha-blocker combined with anticholinergics. LUTS: Lower Urinary Tract Symptoms 2011; 3: 29-35
• 16 Chapple C, Herschorn S, Abrams P et al. Tolterodine treatment improves storage symptoms suggestive of overactive bladder in men treated with alpha-blockers. European urology 2009; 56: 534-543
• 17 Yamaguchi O, Kakizaki H, Homma Y et al. Solifenacin as add-on therapy for overactive bladder symptoms in men treated for lower urinary tract symptoms–ASSIST, randomized controlled study. Urology 2011; 78: 126-133
• 18 Takeda M, Nishizawa O, Gotoh M et al. Clinical efficacy and safety of imidafenacin as add-on treatment for persistent overactive bladder symptoms despite α-blocker treatment in patients with BPH: the ADDITION study. Urology 2013; 82: 887-893
• 19 Homma Y, Paick JS, Lee JG et al. Clinical efficacy and tolerability of extended-release tolterodine and immediate-release oxybutynin in Japanese and Korean patients with an overactive bladder: a randomized, placebo-controlled trial. BJU international 2003; 92: 741-747
• 20 Streng T, Santti R, Talo A. Similarities and differences in female and male rat voiding. Neurourology and urodynamics 2002; 21: 136-141
• 21 Nagabukuro H, Hashimoto T, Iwata M et al. Effects of TAK-802, a novel acetylcholinesterase inhibitor, and tamsulosin, an alpha1-adrenoceptor antagonist, and their synergistic effects on the urodynamic characteristics in a guinea-pig model of functional bladder outlet obstruction. BJU international 2005; 95: 1071-1076
• 22 Knepper SM, Buckner SA, Brune ME et al. A-61603, a potent alpha 1-adrenergic receptor agonist, selective for the alpha 1A receptor subtype. The Journal of pharmacology and experimental therapeutics 1995; 274: 97-103
• 23 Ney P, Pandita RK, Newgreen DT et al. Pharmacological characterization of a novel investigational antimuscarinic drug, fesoterodine, in vitro and in vivo. BJU international 2008; 101: 1036-1042
• 24 Nagabukuro H, Villa KL, Wickham LA et al. Comparative analysis of the effects of antimuscarinic agents on bladder functions in both nonhuman primates and rodents. Journal of pharmacology and experimental therapeutics 2011; 338: 220-227
• 25 Yamada S, Seki M, Ogoda M et al. Selective binding of bladder muscarinic receptors in relation to the pharmacokinetics of a novel antimuscarinic agent, imidafenacin, to treat overactive bladder. The Journal of pharmacology and experimental therapeutics 2011; 336: 365-371
• 26 Mansfield K. Muscarinic receptor antagonists, the overactive bladder and efficacy against urinary urgency. Clinical Medicine Insights: Therapeutics 2010; 2: 471-480
• 27 Ohno T, Nakade S, Nakayama K et al. Absolute bioavailability of imidafenacin after oral administration to healthy subjects. British journal of clinical pharmacology 2008; 65: 197-202
• 28 Andersson K-E, Fullhase C, Soler R. Urothelial effects of oral agents for overactive bladder. Current urology reports 2008; 9: 459-464
• 29 Yono M, Yoshida M, Wada Y et al. Pharmacological effects of tolterodine on human isolated urinary bladder. European journal of pharmacology 1999; 368: 223-230
• 30 Davila GW, Daugherty CA, Sanders SW. A short-term, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. The Journal of urology 2001; 166: 140-145