Abstract
Tolterodine, a nonselective muscarinic antagonist available only as immediate release (IR) or extended release (ER) oral formulations, is used for the treatment of overactive bladder (OAB). This study aimed to compare the efficacy and extent of dry mouth adverse effects of tolterodine transdermal patch to the oral formulation. The two formulations have been examined through the muscarinic receptor binding tests conducted in bladder and salivary gland tissues and the salivary secretion tests conducted in rats. Comparable average tolterodine blood concentration levels were obtained 3 h after oral administration of tolterodine 25 mg/kg and 12 h after transdermal application of tolterodine patch 6 mg/8 cm2. While Kd in the bladder tissue increased to a similar degree in both formulations of tolterodine, Kd in the salivary gland increased to a greater degree in the oral formulation. These results indicate that similar degree of inhibitory effects were observed in the bladder for both formulations while less inhibitory effects were observed in the salivary gland with tolterodine transdermal formulation compared to the oral formulation. For assessment of salivary secretion, tolterodine transdermal patch 6 mg/8 cm2 application resulted in significantly less inhibitory effects than oral tolterodine 25 mg/kg. Therefore, this study suggests that tolterodine transdermal patch could be a useful formulation that provides uniform and consistent inhibitory effects to effectively control OAB symptoms with reduced severity of dry mouth in comparison to the oral formulation.
Similar content being viewed by others
References
Abrams P, Andersson KE (2007) Muscarinic receptor antagonists for overactive bladder. BJU Int 100:987–1006
Abrams P, Freeman R, Anderström C, Mattiasson A (1998) Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol 81:801–810
Anderson RU, Mobley D, Blank B, Saltzstein D, Susset J, Brown JS (1999) Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. J Urol 161:1809–1812
Andersson KE (2016) Potential future pharmacological treatment of bladder dysfunction. Basic Clin Pharmacol Toxicol 119(Suppl 3):75–85
Andersson KE, Wein AJ (2004) Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol Rev 56:581–631
Andersson KE, Yoshida M (2003) Antimuscarinics and the overactive detrusor—which is the main mechanism of action? Eur Urol 43:1–5
Appell RA, Sand P, Dmochowski R, Anderson R, Zinner N, Lama D, Roach M, Miklos J, Saltzstein D, Boone T, Staskin DR, Albrecht D, Overactive Bladder: Judging Effective Control and Treatment Study Group (2001) Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study. Mayo Clin Proc 76:358–363
Armstrong RB, Luber KM, Peters KM (2005) Comparison of dry mouth in women treated with extended-release formulations of oxybutynin or tolterodine for overactive bladder. Int Urol Nephrol 37:247–252
Byeon JY, Kim YH, Na HS, Jang JH, Kim SH, Lee YJ, Bae JW, Kim IS, Jang CG, Chung MW, Lee SY (2015) Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites. Arch Pharm Res 38:2083–2091
Caulfield MP (1993) Muscarinic receptors—characterization, coupling and function. Pharmacol Ther 58:319–379
Chapple CR, Yamanishi T, Chess-Williams R (2002) Muscarinic receptor subtypes and management of the overactive bladder. Urology 60:82–88
Chaudhry SR, Muhammad S, Eidens M, Klemm M, Khan D, Efferth T, Weisshaar MP (2014) Pharmacogenetic prediction of individual variability in drug response based on CYP2D6, CYP2C9 and CYP2C19 genetic polymorphisms. Curr Drug Metab 15:711–718
Chu FM, Dmochowski R (2006) Pathophysiology of overactive bladder. Am J Med 119:3–8
Cohn JA, Brown ET, Reynolds WS, Kaufman MR, Milam DF, Dmochowski PR (2016) An update on the use of transdermal oxybutynin in the management of overactive bladder disorder. Ther Adv Urol 8:83–90
Diokno AC, Appell RA, Sand PK, Dmochowski PR, Gburek BM, Klimberg IW, Kell SH, OPERA Study Group (2003) Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc 78:687–695
Elshafeey AH, Kamel AO, Fathallah MM (2009) Utility of nanosized microemulsion for transdermal delivery of tolterodine tartrate: ex vivo permeation and in vivo pharmacokinetic studies. Pharm Res 26:2446–2453
Erdem N, Chu FM (2006) Management of overactive bladder and urge urinary incontinence in the elderly patient. Am J Med 119:29–36
Giraldo E, Martos F, Gomez A, Garcia A, Vigano MA, Ladinsky H, Sanchez de La Cuesta F (1988) Characterization of muscarinic receptor subtypes in human tissues. Life Sci 43:1507–1515
Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, Monga A, Petri E, Rizk DE, Sand PK, Schaer GN (2010) An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J 21:5–26
Herbison P, Hay-Smith J, Ellis G, Moore K (2003) Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ 326:841–844
Hulme EC, Birdsall NJ, Buckley NJ (1990) Muscarinic receptor subtypes. Ann Rev Pharmacol Toxicol 30:633–673
Kim SH, Kim DH, Byeon JY, Kim YH, Kim DH, Lim HJ, Lee CM, Whang SS, Choi CI, Bae JW, Lee YJ, Jang CG, Lee SY (2017a) Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of celecoxib and it’s carboxylic acid metabolite. Arch Pharm Res 40:382–390
Kim YH, Byeon JY, Kim SH, Lee CM, Lee YJ, Jang CG, Lee SY (2017b) Simultaneous determination of tolterodine and its two metabolites, 5-hydroxymethyltolterodine and N-dealkyltolterodine in human plasma using LC–MS/MS and its application to a pharmacokinetic study. Arch Pharm Res 40:1287–1295. https://doi.org/10.1007/s12272-017-0981-3
Lee YJ, Byeon JY, Kim YH, Kim SH, Choi CI, Bae JW, Sohn UD, Jang CG, Lee J, Lee SY (2015) Effects of CYP2C9*1/*3 genotype on the pharmacokinetics of flurbiprofen in Korean subjects. Arch Pharm Res 38:1232–1237
Lee HJ, Kim YH, Kim SH, Lee CM, Yang AY, Jang CG, Lee SY, Bae JW, Choi CI (2016) Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of zafirlukast. Arch Pharm Res 39:1013–1019
Liu J, Wang Z, Liu C, Xi H, Li C, Chen Y, Sun L, Mu L, Fang L (2012) Silicone adhesive, a better matrix for tolterodine patches-a research based on in vitro/in vivo studies. Drug Dev Ind Pharm 38:1008–1014
Liu X, Fu L, Dai W, Liu W, Zhao J, Wu Y, Teng L, Sun F, Li Y (2014) Design of transparent film-forming hydrogels of tolterodine and their effects on stratum corneum. Int J Pharm 471:322–331
Liu W, Teng L, Yu K, Sun X, Fan C, Long C, Liu N, Li S, Wu B, Xu Q, Sun F, Li Y (2017) Design of hydrogels of 5-hydroxymethyl tolterodine and their studies on pharmacokinetics, pharmacodynamics and transdermal mechanism. Eur J Pharm Sci 96:530–541
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Nilvebrant L (2002) Tolterodine and its active 5-hydroxymethyl metabolite: pure muscarinic receptor antagonists. Pharmacol Toxicol 90:260–267
Nilvebrant L, Hallén B, Larsson G (1997) Tolterodine—a new bladder selective muscarinic receptor antagonist: preclinical pharmacological and clinical data. Life Sci 60:1129–1136
Oki T, Maruyama S, Takagi Y, Yamamura HI, Yamada S (2006a) Characterization of muscarinic receptor binding and inhibition of salivation after oral administration of tolterodine in mice. Eur J Pharmacol 529:157–163
Oki T, Toma-Okura A, Yamada S (2006b) Advantages for transdermal over oral oxybutynin to treat overactive bladder: muscarinic receptor binding, plasma drug concentration, and salivary secretion. J Pharmacol Exp Ther 316:1137–1145
Ouslander JG (2004) Management of overactive bladder. N Eng J Med 350:786–799
Påhlman I, d’Argy R, Nilvebrant L (2001) Tissue distribution of tolterodine, a muscarinic receptor antagonist, and transfer into fetus and milk in mice. Arzneimittelforschung 51:125–133
Postlind H, Danielson A, Lindgren A, Andersson SH (1998) Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes. Drug Metab Dispos 26:289–293
Rajabalaya R, Leen G, Chellian J, Chakravarthi S, David SR (2016) Tolterodine tartrate proniosomal gel transdermal delivery for overactive bladder. Pharmaceutics 8:E27
Sathyan G, Chancellor MB, Gupta SK (2001) Effect of OROS controlled-release delivery on the pharmacokinetics and pharmacodynamics of oxybutynin chloride. Br J Clin Pharmacol 52:409–417
Staskin DR, MacDiarmid SA (2006) Using anticholinergics to treat overactive bladder: the issue of treatment tolerability. Am J Med 119:9–15
Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, Hunt TL, Wein AJ (2003) Prevalence and burden of overactive bladder in the United States. World J Urol 20:327–336
Sun F, Sui C, Zhou Y, Liu X, Shi Y, Wu Y, Li Y (2013) Preparation, characterization and pharmacological evaluation of tolterodine hydrogels for the treatment of overactive bladder. Int J Pharm 454:532–538
Sussman D, Garely A (2002) Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET). Curr Med Res Opin 18:177–1784
Thiagamoorthy G, Cardozo L, Robinson D (2016) Current and future pharmacotherapy for treating overactive bladder. Expert Opin Pharmacother 17:1317–1325
Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A, Tolterodine Study Group (2001) Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology 57:414–421
Vouri SM, Kebodeaux CD, Stranges PM, Teshome BF (2017) Adverse events and treatment discontinuations of antimuscarinics for the treatment of overactive bladder in older adults: a systematic review and meta-analysis. Arch Gerontol Geriatr 69:77–96
Wagg A, Nitti VW, Kelleher C, Castro-Diaz D, Siddiqui E, Berner T (2016) Oral pharmacotherapy for overactive bladder in older patients: mirabegron as a potential alternative to antimuscarinics. Curr Med Res Opin 32:621–638
Wang P, Luthin GR, Ruggieri MR (1995) Muscarinic acetylcholine receptor subtypes mediating urinary bladder contractility and coupling to GTP binding proteins. J Pharmacol Exp Ther 273:959–966
Werk AN, Cascorbi I (2014) Functional gene variants of CYP3A4. Clin Pharmacol Ther 96:340–348
Willis-Gray MG, Dieter AA, Geller EJ (2016) Evaluation and management of overactive bladder: strategies for optimizing care. Res Rep Urol 8:113–122
Yamada S, Kuraoka S, Osano A, Ito Y (2012) Characterization of bladder selectivity of antimuscarinic agents on the basis of in vivo drug-receptor binding. Int Neurourol J 16:107–115
Funding
The funding is provided by SK Chemicals Life Science.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
We have no conflict of interest to declare other than that this study was supported by the research fund from SK Chemicals Life Science, South Korea.
Rights and permissions
About this article
Cite this article
Byeon, JY., Kim, YH., Kim, SH. et al. Inhibition of salivary secretion by tolterodine transdermal patch. Arch. Pharm. Res. 40, 1455–1463 (2017). https://doi.org/10.1007/s12272-017-0988-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-017-0988-9