Abstract
Antagonists of muscarinic acetylcholine receptors, such as darifenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium, are the mainstay of the treatment of the overactive bladder syndrome. Fesoterodine is a newer drug awaiting regulatory approval. We briefly review the pharmacological activity of their metabolites and discuss how active metabolites may contribute to their efficacy and tolerability in vivo. Except for trospium, and perhaps solifenacin, all of the above drugs form active metabolites, and their presence and activity need to be taken into consideration when elucidating relationships between pharmacokinetics and pharmacodynamics of these drugs. Moreover, the ratios between parent compounds and metabolites may differ depending on genotype of the metabolizing enzymes, concomitant medication, and/or drug formulation. Differential generation of active metabolites of darifenacin or tolterodine are unlikely to influence the overall clinical profile of these drugs in a major way because the active metabolites exhibit a similar pharmacological profile as the parent compound. In contrast, metabolites of oxybutynin and propiverine may behave quantitatively or even qualitatively differently from their parent compounds and this may have an impact on the overall clinical profile of these drugs. We conclude that more comprehensive studies of drug metabolites are required for an improved understanding of their clinical effects.
References
Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A (2002) The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Neurourol Urodyn 21:167–178
Beaumont KC, Cussans NJ, Nichols DJ, Smith DA (1998) Pharmacokinetics and metabolism of darifenacin in the mouse, rat, dog and man. Xenobiotica 28:63–75
Borchert VE, Czyborra P, Fetscher C, Goepel M, Michel MC (2004) Extracts from Rhois aromatica and Solidaginis vigaurea inhibit rat and human bladder contraction. Naunyn-Schmiedeberg’s Arch Pharmacol 369:281–286
Brynne N, Stahl MM, Hallen B, Edlund PO, Palmer L, Hoglund P, Gabrielsson J (1997) Pharmacokinetics and pharmacodynamics of tolterodine in man: a new drug for the treatment of urinary bladder overactivity. Int J Clin Pharmacol Ther 35:287–295
Brynne N, Dalen P, Alvan G, Bertilsson L, Gabrielsson J (1998) Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of tolterodine. Clin Pharmacol Ther 63:529–539
Burk O, Wojnowski L (2004) Cytochrome P450 3A4 and their regulation. Naunyn-Schmiedeberg’s Arch Pharmacol 369:105–124
Buyse G, Waldeck K, Verpoorten C, Björk H, Casaer P, Andersson K-E (1998) Intravesical oxybutynin for neurogenic bladder dysfunction: less systemic side effects due to reduced first pass metabolism. J Urol 160:892–896
Chapple C, Khullar V, Gabriel Z, Dooley JA (2005) The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 48:5–26
Cole P (2004) Fesoterodine, an advanced antimuscarinic for the treatment of overactive bladder: a safety update. Drugs Fut 29:715–720
Davila GW, Daugherty CA, Sanders SW (2001) A short-term, multicenter, randomized double-blind dose titration study of the efficacy and anticholingeric side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J Urol 166:140–145
Dmochowski R, Chen A, Sathyan G, MacDiarmid S, Gidwani S, Gupta S (2005a) Effect of the proton pump inhibitor omeprazole on the pharmacokinetics of extended-release formulations of oxybutynin and tolterodine. J Clin Pharmacol 45:961–968
Dmochowski RR, Nitti V, Staskin D, Luber K, Appell R, Davila GW (2005b) Transdermal oxybutynin in the treatment of adults with overactive bladder: combined results of two randomized clinical trials. World J Urol 23:263–270
Doroshyenko O, Jetter A, Odenthal KP, Fuhr U (2005) Clinical pharmacokinetics of trospium chloride. Clin Pharmacokin 44:701–720
Douchamps J, Derenne F, Stockis A, Gangji D, Juvent M, Herchhuelz A (1988) The pharmacokinetics of oxybutynin in man. Eur J Clin Pharmacol 35:515–520
Gerloff T (2004) Impact of genetic polymorphisms in transmembrane carrier-systems on drug and xenobiotic distribution. Naunyn-Schmiedeberg’s Arch Pharmacol 369:69–77
Guay DRP (2003) Clinical pharmacokinetics of drugs used to treat urge incontinence. Clin Pharmacokin 42:1243–1285
Gupta SK, Sathyan G (1999) Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin. J Clin Pharmacol 39:289–296
Haustein KO, Huller G (1988) On the pharmacokinetics and metabolism of propiverine in man. Eur J Drug Metab Pharmacokinet 13:81–90
Hegde SS (2006) Muscarinic receptors in the bladder: from basic research to therapeutics. Br J Pharmacol 147:S80–S87
Hughes KM, Lang JCT, Lazare R, Gordon D, Stanton SL, Malone-Lee J, Geraint M (1992) Measurement of oxybutynin and its N-desethyl metabolite in plasma, and its application to pharmacokinetic studies in young, elderly and frail elderly volunteers. Xenobiotica 22:859–869
Kerbusch T, Milligan PA, Karlsson MO (2003) Assessment of the relative in vivo potency of the hydroxylated metabolite of darifenacin in its ability to decrease salivary flow using pooled population pharmacokinetic-pharmacodynamic data. Br J Clin Pharmacol 57:170–180
Krauwinkel WJ, Smulders RA, Mulder H, Swart PJ, Taekema-Roelvink ME (2005) Effect of age on the pharmacokinetics of solifenacin in men and women. Int J Clin Pharmacol Ther 43:227–238
Lukkari E, Juhakoski A, Aranko K, Neuvonen PJ (1997) Itraconazole moderately increases serum concentrations of oxybutynin but does not affect those of the active metabolite. Eur J Clin Pharmacol 52:403–406
Lukkari E, Taavitsainen P, Juhakoski A, Pelkonen O (1998) Cytochrome P450 specificity of metabolism and interactions of oxybutynin in human liver microsomes. Pharmacol Toxicol 82:161–166
Madersbacher H, Mürtz G (2001) Efficacy, tolerability and safety profile of propiverine in the treatment of the overactive bladder (non-neurogenic and neurogenic). World J Urol 19:324–335
Michel MC (2002) A benefit-risk assessment of extended-release oxybutynin. Drug Safety 25:867–876
Michel MC, Yanagihara T, Minematsu T, Swart PJ, Smulders RA (2005) Disposition and metabolism of solifenacin in humans. Br J Clin Pharmacol 59:647
Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff JW, Wein AJ (2001) How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 87:760–766
Müller C, Siegmund W, Huupponen R, Kaila T, Franke G, Iisalo E, Zschiesche M (1993) Kinetics of propiverine as assessed by radioreceptor assay in poor and extensive metabolizers of debrisoquine. Eur J Drug Metab Pharmacokinet 18:265–272
Nilvebrant L (2002) Tolterodine and its active 5-hydroxymethyl metabolite: pure muscarinic receptor antagonists. Pharmacol Toxicol 90:260–267
Nilvebrant L, Hallen B, Larsson G (1997) Tolterodine - a new bladder selective muscarinic receptor antagonist: preclinical pharmacological and clinical data. Life Sci 60:1129–1136
Oki T, Kimura R, Saito M, Miyagawa I, Yamada S (2004) Demonstration of bladder selective muscarinic receptor binding by intravesical oxybutynin to treat overactive bladder. J Urol 172:2059–2064
Oki T, Kawashima A, Uchida M, Yamada S (2005a) In vivo demonstration of muscarinic receptor binding activity of N-desethyl-oxybutynin, active metabolite of oxybutynin. Life Sci 76:2445–2456
Oki T, Sato S, Miyata K, Yamada S (2005b) Muscarinic receptor binding, plasma concentration and inhibition of salivation after oral administration of a novel antimuscarinic agent, solifenacin succinate in mice. Br J Pharmacol 145:219–227
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
Olsson B, Szamosi J (2001) Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release formulation. Clin Pharmacokin 40:227–235
Postlind H, Dnielson A, Lindgren A, Andersson SHG (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
Sathyan G, Chancellor MB, Gupta SK (2001a) Effects of OROS controlled-release delivery on the pharmacokinetics and pharmacodynamics of oxybutynin chloride. Br J Clin Pharmacol 52:409–418
Sathyan G, Hu W, Gupta SK (2001b) Lack of effect of food on the pharmacokinetics of an extended-release oxybutynin formulation. J Clin Pharmacol 41:187–192
Schneider T, Hein P, Michel-Reher M, Michel MC (2005) Effects of ageing on muscarinic receptor subtypes and function in rat urinary bladder. Naunyn-Schmiedeberg’s Arch Pharmacol 372:71–78
Shibukawa A, Yoshikawa Y, Kimura T, Kuroda Y, Nakagawa T, Wainer IW (2002) Binding study of desethyloxybutynin using high-performance frontal analysis method. J Chromatography 768:189–197
Siepmann M, Nokhodian A, Thümmler D, Kirch W (1998) Pharmacokinetics and safety of propiverine in patients with fatty liver disease. Eur J Clin Pharmacol 54:767–771
Skerjanec A (2006) The clinical pharmacokinetics of darifenacin. Clin Pharmacokin 45:325–350
Uchida M, Koganei M, Murata N, Yamaji T (2004) Effects of 4-ethylamino-2-butynyl(2-cyclohexyl-2-phenyl)glycolate hydrochloride, a metabolite of oxybutynin, on bladder specimens and rhythmic contraction in rats in comparison with oxybutynin. J Pharmacol Sci 94:122–128
van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A (2001) Tolterodine once-daily: superior efficacy and tolerability in the treatment of overactive bladder. Urology 57:414–421
Waldeck K, Larsson B, Andersson K-E (1997) Comparison of oxybutynin and its active metabolite, N-desethyl-oxybutynin, in the human detrusor and parotid gland. J Urol 157:1093–1097
Wuest M, Braeter M, Schoeberl C, Ravens U (2005a) Juvenile pig detrusor: effects of propiverine and three of its metabolites. Eur J Pharmacol 524:145–148
Wuest M, Hecht J, Christ T, Braeter M, Schoeberl C, Hakenberg OW, Wirth MP, Ravens U (2005b) Pharmacodynamics of propiverine and three of its metabolites on detrusor contraction. Br J Pharmacol 145:608–619
Wuest M, Morgenstern K, Graf E-M, Braeter M, Hakenberg OW, Wirth MP, Ravens U (2005c) Cholinergic and purinergic responses in isolated human detrusor in relation to age. J Urol 173:2182–2189
Wuest M, Weiss A, Waelbrock M, Braeter M, Kelly L-U, Hakenberg OW, Ravens U (2006) Propiverine and metabolites: differences in binding to muscarinic receptors and in functional models of detrusor contraction. Naunyn-Schmiedeberg’s Arch Pharmacol (in press). DOI 10.1007/s00210-006-103-0
Yaich M, Popon M, Medard Y, Aigrain EJ (1998) In-vitro cytochrome P450 dependent metabolism of oxybutynin to N-deethyloxybutynin in humans. Pharmacogenetics 8:449–451
Yono M, Yoshida M, Wada Y, Kikukawa H, Takahashi W, Inadome A, Seshita H, Ueda S (1999) Pharmacological effects of tolterodine on human isolated urinary bladder. Eur J Pharmacol 368:223–230
Zanger UM, Raimundo S, Eichelbaum M (2004) Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn-Schmiedeberg’s Arch Pharmacol 369:23–37
Zobrist RH, Schmid B, Feick A, Quan D, Sanders SW (2001) Pharmacokinetics of the R- and S-enantiomers of oxybutynin and N-desethyloxybutynin following oral and transdermal administration of the racemate in healthy volunteers. Pharm Res 18:1029–1034
Zobrist RH, Quan D, Thomas HM, Stanworth S, Sanders SW (2003) Pharmacokinetics and metabolism of transdermal oxybutynin: in vitro and in vivo performance of a novel delivery system. Pharm Res 20:103–109
Conflict of interest statement
In the therapeutic area of OAB, M.C.M. has received research funds and/or consultancy or lecture honoraria within the last five years from the following companies: 4SC, Apogepha, Astellas, Bayer, Boehringer Ingelheim, Pfizer and Theravance. S.S.H. is an employee of a company with an interest in OAB.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Michel, M.C., Hegde, S.S. Treatment of the overactive bladder syndrome with muscarinic receptor antagonists - a matter of metabolites?. Naunyn-Schmied Arch Pharmacol 374, 79–85 (2006). https://doi.org/10.1007/s00210-006-0105-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-006-0105-y