Treatment Of Urge Urinary Incontinence Research Articles

Behavioral vs. Drug Treatment for Urge Urinary Incontinence in Older Women. A Randomized Controlled Trial

Context.—Urinary incontinence is a common condition caused by many factors with several treatment options. Objective.—To compare the effectiveness of biofeedback-assisted behavioral treatment with drug treatment and a placebo control condition for the treatment of urge and mixed urinary incontinence in older community-dwelling women. Design.—Randomized placebo-controlled trial conducted from 1989 to 1995. Setting.—University-based outpatient geriatric medicine clinic. Patients.—A volunteer sample of 197 women aged 55 to 92 years with urge urinary incontinence or mixed incontinence with urge as the predominant pattern. Subjects had to have urodynamic evidence of bladder dysfunction, be ambulatory, and not have dementia. Intervention.—Subjects were randomized to 4 sessions (8 weeks) of biofeedback-assisted behavioral treatment, drug treatment (with oxybutynin chloride, possible range of doses, 2.5 mg daily to 5.0 mg 3 times daily), or a placebo control condition. Main Outcome Measures.—Reduction in the frequency of incontinent episodes as determined by bladder diaries, and patients’ perceptions of improvement and their comfort and satisfaction with treatment. Results.—For all 3 treatment groups, reduction of incontinence was most pronounced early in treatment and progressed more gradually thereafter. Behavioral treatment, which yielded a mean 80.7% reduction of incontinence episodes, was significantly more effective than drug treatment (mean 68.5% reduction; P = .04) and both were more effective than the placebo control condition (mean 39.4% reduction; P,.001 and P = .009, respectively). Patient-perceived improvement was greatest for behavioral treatment (74.1% “much better” vs 50.9% and 26.9% for drug treatment and placebo, respectively). Only 14.0% of patients receiving behavioral treatment wanted to change to another treatment vs 75.5% in each of the other groups. Conclusion.—Behavioral treatment is a safe and effective conservative intervention that should be made more readily available to patients as a first-line treatment for urge and mixed incontinence. JAMA. 1998;280:1995-2000

Behavioral vs. Drug Treatment for Urge Urinary Incontinence in Older Women. A Randomized Controlled Trial

Behavioral vs. Drug Treatment for Urge Urinary Incontinence in Older Women. A Randomized Controlled Trial

Pharmacokinetics of an Oral Once‐a‐Day Controlled‐Release Oxybutynin Formulation Compared with Immediate‐Release Oxybutynin

Oxybutynin is used for the treatment of urge urinary incontinence. In this randomized, open-label, two-way crossover, multiple-dose study, the pharmacokinetics of a once-daily, controlled-release formulation, OROS oxybutynin chloride, was compared with that of immediate-release (IR) oxybutynin (Ditropan). Thirteen healthy female volunteers received three 5 mg OROS oxybutynin chloride tablets once daily for 4 days or IR oxybutynin 5 mg administered every 8 hours for 4 days. On day 1, with OROS oxybutynin chloride, mean plasma concentrations rose slowly over approximately 6 hours following dosing (mean Cmax 4.2 ng/mL) and remained fairly constant over the 24-hour dosing interval, whereas with IR oxybutynin, mean plasma concentrations rose rapidly within the first hour after dosing (mean Cmax 12.0 ng/mL), then declined. The mean oxybutynin degree of fluctuation was much lower for OROS oxybutynin chloride (78%) than for IR oxybutynin (371%). For both formulations, the plasma concentration-time profiles for the metabolite N-desethyloxybutynin paralleled those of oxybutynin but at higher concentrations. Steady-state oxybutynin concentrations were achieved by day 3 for both formulations. Mean area under the concentration-time curve (AUC) values for both oxybutynin and its metabolite were similar between day 1 and day 4 for each treatment, suggesting time-invariant pharmacokinetics. With OROS oxybutynin chloride, mean relative bioavailability was higher (153%) for oxybutynin and lower (69%) for N-desethyloxybutynin compared with IR oxybutynin. This increased bioavailability may be due to reduced first-pass metabolism; within 3 to 5 hours after dosing, OROS systems are thought to reach the colon, where cytochrome P450-mediated oxidation (oxybutynin's primary metabolic pathway) may be less extensive than in the small intestine. Fewer subjects reported any adverse event with OROS oxybutynin chloride than with IR oxybutynin (including dry mouth, oxybutynin's most frequently reported anticholinergic adverse effect).

P–302 - Antimuscarinic effect of AH-9700, a novel centrally and peripherally acting drug for treatment of urge urinary incontinence, on rat bladder

P–302 - Antimuscarinic effect of AH-9700, a novel centrally and peripherally acting drug for treatment of urge urinary incontinence, on rat bladder

Tolterodine-A New Bladder-Selective Antimuscarinic Agent

Tolterodine is a new muscarinic receptor antagonist intended for the treatment of urinary urge incontinence and other symptoms related to an overactive bladder. The aim of the present study was to compare the antimuscarinic properties of tolterodine with those of oxybutynin, in vitro and in vivo. Tolterodine effectively inhibited carbachol-induced contractions of isolated strips of urinary bladder from guinea pigs (K(B) 3.0 nM; pA2 8.6; Schild slope 0.97) and humans (K(B) 4.0 nM; pA2 8.4; Schild slope 1.04) in a concentration-dependent, competitive manner. The affinity of tolterodine was similar to that derived for oxybutynin (K(B) 4.4 nM; pA2 8.5; Schild slope 0.89) in the guinea-pig bladder. Tolterodine (21-2103 nmol/kg (0.01-1 mg/kg); intravenous infusion) was significantly more potent in inhibiting acetylcholine-induced urinary bladder contraction than electrically-induced salivation in the anaesthetised cat. In contrast, oxybutynin displayed the opposite tissue selectivity. Radioligand binding data showed that tolterodine bound with high affinity to muscarinic receptors in urinary bladder (K(i) 2.7 nM), heart (K(i) 1.6 nM), cerebral cortex (K(i) 0.75 nM) and parotid gland (K(i) 4.8 nM) from guinea pigs and in urinary bladder from humans (K(i) 3.3 nM). Tolterodine and oxybutynin were equipotent, except in the parotid gland, where oxybutynin bound with 8-times higher affinity (K(i) 0.62 nM). Binding data on human muscarinic m1-m5 receptors expressed in Chinese hamster ovary cells showed that oxybutynin, in contrast to tolterodine, exhibits selectivity (10-fold) for muscarinic m3 over m2 receptors. The K(B) value determined for oxybutynin (4.4 nM) in functional studies on guinea-pig bladder correlated better with the binding affinity at muscarinic M2/m2 receptors (K(i) 2.8 and 6.7 nM) than at muscarinic M3/m3 receptors (K(i) 0.62 and 0.67 nM). The tissue selectivity demonstrated for tolterodine in vivo cannot be attributed to selectivity for a single muscarinic receptor subtype. However, the combined in vitro and in vivo data on tolterodine and oxybutynin may indicate either that muscarinic M3/m3 receptors in glands are more sensitive to blockade than those in bladder smooth muscle, or that muscarinic M2/m2 receptors contribute to bladder contraction.

Urinary urge incontinence

Urinary incontinence, the involuntary loss of urine, is a prevalent medical condition that affects men, women and children of all ages. However, the incidence of incontinence tends to increase with age and it is particularly widespread in the elderly. Four major categories of incontinence have been defined: urge incontinence, stress incontinence, overflow incontinence and functional incontinence. Urinary urge incontinence (UUI) is the largest category affecting both men and women and is also the most amenable to pharmacological intervention. A large number of patients suffer from this condition (ca. 20 million). However, existing pharmaceutical agents for the treatment of UUI either lack efficacy or are poorly tolerated and, consequently, the condition is poorly controlled. Thus, there is a high medical need for efficacious, well-tolerated drugs to treat this condition. The commercial potential for novel, effective agents is considerable, given the number of patients involved and the growth associated wit...

Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists

Tolterodine [( R)- N, N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine] is a new potent and competitive muscarinic receptor antagonist developed for the treatment of urinary urge incontinence and other symptoms of overactive bladder. In vivo, tolterodine exhibits functional selectivity for the urinary bladder over salivary glands, a profile that cannot be explained in terms of selectivity for a single muscarinic receptor subtype. The aim of this study was to compare the in vitro and in vivo antimuscarinic profiles of tolterodine with those of muscarinic receptor antagonists with distinct receptor subtype-selectivity profiles: darifenacin [( S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide; selective for muscarinic M 3 receptors]; UH-AH 37 (6-chloro-5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H-dibenzo-[ b, e][1,4]diazepine-11-one; low affinity for muscarinic M 2 receptors); and AQ-RA 741 (11-({4-[4-(diethylamino)butyl]-1-piperidinyl}acetyl)-5,11-dihydro-6H-pyrido[2,3- b][1,4]benzodiazepine-6-one; high affinity for muscarinic M 2 receptors). The in vitro profiles of these compounds were in agreement with previous reports; darifenacin and UH-AH 37 demonstrated selectivity for muscarinic M 3/m3 over M 2/m2 receptors, while the converse was observed for AQ-RA 741. In vivo, AQ-RA 741 was more potent (1.4–2.7-fold) in inhibiting urinary bladder contraction than salivation in the anaesthetised cat (i.e., a profile similar to that of tolterodine [2.5–3.3-fold]), while darifenacin and UH-AH 37 showed the reverse selectivity profile (0.6–0.8 and 0.4–0.5-fold, respectively). The results confirm that it is possible to separate the antimuscarinic effects on urinary bladder and salivary glands in vivo. The data on UH-AH 37 and darifenacin support the view that a selectivity for muscarinic M 3/m3 over M 2/m2 receptors may result in a more pronounced effect on salivation than on bladder contraction. The data on AQ-RA 741 may indicate that muscarinic M 2/m2 receptors may have a role in bladder contraction.

Biofeedback for community-dwelling individuals with urinary incontinence

Objectives. To review the role of biofeedback in the management of community-dwelling individuals with urge urinary incontinence (UUI), and to present a practical approach to patient evaluation and treatment selection. Methods. In view of a lack of objective published information, perspectives on the use of biofeedback in UUI are derived from extrapolation of studies in patients with stress incontinence as well as from the author's personal experience. Results. Through the use of careful baseline evaluations, appropriate exercise and biofeedback treatment for UUI can be selected for specific patients. Office-based biofeedback is preferred for patients who have no or minimal ability to isolate and contract the levator muscles at baseline. Such individuals cannot be expected to exercise effectively without instruction but can be converted to home-based treatment once responses have been achieved. Patients with weak contractions but appropriate muscle isolation are appropriate candidates for Kegel exercises; biofeedback has not been conclusively demonstrated to be superior to exercise therapy alone in this group. Vaginal cones or simple home biofeedback units may be useful adjuncts in these cases. Patients who have good muscle isolation and strong pelvic contractions at baseline generally have more severe bladder dysfunction and require aggressive treatment aimed at the detrusor. Instruction in “quick flicks” may assist in inhibiting urgency, and motivated patients may be offered vaginal cones. Conclusions. Pelvic floor muscle dysfunction is an important but often-overlooked component of UUI. The algorithm presented here can assist in tailoring exercise and biofeedback therapy to the individual patient. However, more research is needed to help stratify patients according to the degree of detrusor dysfunction and status of pelvic floor muscles before intervention.

Selective muscarinic antagonists. II. Synthesis and antimuscarinic properties of biphenylylcarbamate derivatives.

A novel series of biphenylylcarbamate derivatives were synthesized and evaluated for binding to M1, M2 and M3 receptors and for antimuscarinic activities. Receptor binding assays indicated that biphenyl-2-ylcarbamate derivatives had high affinities for M1 and M3 receptors and good selectivities for M3 receptor over M2 receptor, indicating that the biphenyl-2-yl group is a novel hydrophobic replacement for the benzhydryl group in the muscarinic antagonist field. In this series, quinuclidin-4-yl biphenyl-2-ylcarbamate monohydrochloride (8l, YM-46303) exhibited the highest affinities for M1 and M3 receptors, and selectivity for M3 over M2 receptor. Compared to oxybutynin, YM-46303 showed approximately ten times higher inhibitory activity on bladder pressure in reflexly-evoked rhythmic contraction, and about 5-fold greater selectivity for urinary bladder contraction against salivary secretion in rats. Moreover, selective antagonistic activity was also observed in vitro. Further evaluation of antimuscarinic effects on bradycardia and pressor in pithed rats, and on tremor in mice, showed that YM-46303 can be useful for the treatment of urinary urge incontinence as a bladder-selective M3 antagonist with potent activities and fewer side effects.

Selective muscarinic antagonists. I. Synthesis and antimuscarinic properties of 4-piperidyl benzhydrylcarbamate derivatives.

A series of 1-substituted-4-piperidyl benzhydrylcarbamate derivatives were synthesized and evaluated for binding affinity to M1, M2 and M3 receptors, and for antimuscarinic activities. Receptor binding assays indicated that 1-benzyl-4-piperidyl benzhydrylcarbamate derivatives showed higher affinities for M1 and M3 receptors, and good selectivities for M3 over M2 receptor, than the corresponding ester analog. These results indicate that the urethane bond is a novel linker for muscarinic antagonists, and serves to lock the molecular conformation and allows the hydrophobic portion and cationic site of the molecule to bind to M1 and M3 muscarinic receptors. Among the prepared compounds, 1-(4-methylaminobenzyl)-4-piperidyl benzhydrylcarbamate monohydrochloride (18b, YM-58790) exhibited potent inhibitory activity on bladder pressure in reflexly-evoked rhythmic contraction, comparable to oxybutynin and was approximately ten times less inhibitory on oxotremorine-induced salivary secretion than oxybutynin in rats. Further evaluation of antimuscarinic effects on bradycardia and pressor in pithed rats, and on tremor in mice, demonstrated that YM-58790 can be useful for treatment of urinary urge incontinence as a bladder-selective M3 antagonist with fewer side effects.

Tolterodine – a new bladder-selective antimuscarinic agent

Tolterodine is a new muscarinic receptor antagonist intended for the treatment of urinary urge incontinence and other symptoms related to an overactive bladder. The aim of the present study was to compare the antimuscarinic properties of tolterodine with those of oxybutynin, in vitro and in vivo. Tolterodine effectively inhibited carbachol-induced contractions of isolated strips of urinary bladder from guinea pigs ( K B 3.0 nM; pA 2 8.6; Schild slope 0.97) and humans ( K B 4.0 nM; pA 2 8.4; Schild slope 1.04) in a concentration-dependent, competitive manner. The affinity of tolterodine was similar to that derived for oxybutynin ( K B 4.4 nM; pA 2 8.5; Schild slope 0.89) in the guinea-pig bladder. Tolterodine (21–2103 nmol/kg (0.01–1 mg/kg); intravenous infusion) was significantly more potent in inhibiting acetylcholine-induced urinary bladder contraction than electrically-induced salivation in the anaesthetised cat. In contrast, oxybutynin displayed the opposite tissue selectivity. Radioligand binding data showed that tolterodine bound with high affinity to muscarinic receptors in urinary bladder ( K i 2.7 nM), heart ( K i 1.6 nM), cerebral cortex ( K i 0.75 nM) and parotid gland ( K i 4.8 nM) from guinea pigs and in urinary bladder from humans ( K i 3.3 nM). Tolterodine and oxybutynin were equipotent, except in the parotid gland, where oxybutynin bound with 8-times higher affinity ( K i 0.62 nM). Binding data on human muscarinic m1–m5 receptors expressed in Chinese hamster ovary cells showed that oxybutynin, in contrast to tolterodine, exhibits selectivity (10-fold) for muscarinic m3 over m2 receptors. The K B value determined for oxybutynin (4.4 nM) in functional studies on guinea-pig bladder correlated better with the binding affinity at muscarinic M 2/m2 receptors ( K i 2.8 and 6.7 nM) than at muscarinic M 3/m3 receptors ( K i 0.62 and 0.67 nM). The tissue selectivity demonstrated for tolterodine in vivo cannot be attributed to selectivity for a single muscarinic receptor subtype. However, the combined in vitro and in vivo data on tolterodine and oxybutynin may indicate either that muscarinic M 3/m3 receptors in glands are more sensitive to blockade than those in bladder smooth muscle, or that muscarinic M 2/m2 receptors contribute to bladder contraction.

Tolterodine: a new drug for urinary incontinence

Urinary incontinence is estimated to affect more than 30 million people in the developed world. However, while this disorder is treatable and often curable in most individuals, the efficacy and tolerability of currently available therapeutic agents is far from optimal. Tolterodine * is a new muscarinic antagonist specifically developed for the treatment of urinary urge incontinence and other symptoms of detrusor overactivity. In this week’s issue, Inpharma ® maps the progress of this interesting compound in preclinical studies and preliminary phase II clinical trials.

N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides: KATP potassium channel openers. Modifications on the western region.

A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure-activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(-) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.

Inhibition of the renin-angiotensin system and renal lithium excretion

Tolterodine is a new muscarinic receptor antagonist intended for the treatment of urinary urge incontinence and other symptoms related to an overactive bladder. The aim of the present study was to compare the antimuscarinic properties of tolterodine with those of oxybutynin, in vitro and in vivo. Tolterodine effectively inhibited carbachol-induced contractions of isolated strips of urinary bladder from guinea pigs (KB 3.0 nM; pA2 8.6; Schild slope 0.97) and humans (KB 4.0 nM; pA2 8.4; Schild slope 1.04) in a concentration-dependent, competitive manner. The affinity of tolterodine was similar to that derived for oxybutynin (KB 4.4 nM; pA2 8.5; Schild slope 0.89) in the guinea-pig bladder. Tolterodine (21–2103 nmol/kg (0.01–1 mg/kg); intravenous infusion) was significantly more potent in inhibiting acetylcholine-induced urinary bladder contraction than electrically-induced salivation in the anaesthetised cat. In contrast, oxybutynin displayed the opposite tissue selectivity. Radioligand binding data showed that tolterodine bound with high affinity to muscarinic receptors in urinary bladder (Ki 2.7 nM), heart (Ki 1.6 nM), cerebral cortex (Ki 0.75 nM) and parotid gland (Ki 4.8 nM) from guinea pigs and in urinary bladder from humans (Ki 3.3 nM). Tolterodine and oxybutynin were equipotent, except in the parotid gland, where oxybutynin bound with 8-times higher affinity (Ki 0.62 nM). Binding data on human muscarinic m1–m5 receptors expressed in Chinese hamster ovary cells showed that oxybutynin, in contrast to tolterodine, exhibits selectivity (10-fold) for muscarinic m3 over m2 receptors. The KB value determined for oxybutynin (4.4 nM) in functional studies on guinea-pig bladder correlated better with the binding affinity at muscarinic M2/m2 receptors (Ki 2.8 and 6.7 nM) than at muscarinic M3/m3 receptors (Ki 0.62 and 0.67 nM). The tissue selectivity demonstrated for tolterodine in vivo cannot be attributed to selectivity for a single muscarinic receptor subtype. However, the combined in vitro and in vivo data on tolterodine and oxybutynin may indicate either that muscarinic M3/m3 receptors in glands are more sensitive to blockade than those in bladder smooth muscle, or that muscarinic M2/m2 receptors contribute to bladder contraction.

Percutaneous absorption of terodiline and the membrane-controlled transdermal therapeutic system

In an attempt to prepare a transdermal dosage form of terodiline which is extensively metabolized in man, the absorption of terodiline, an anticholinergic and calcium antagonist, through rat skin was estimated in vitro and in vivo. Terodiline penetrated rapidly through the skin from the gel formulation without enhancers (penetration rate, 167.6 μg/h per cm 2). Laurocapram, a potent enhancer, did not enhance the absorption in vitro. When the gel formulation (0.9 g) was applied to rat abdominal skin (6 cm 2), high plasma concentrations ( C max, 8.8±3.4 μg/ ml) of terodiline were observed for 24 h, thereby resulting in a high bioavailability equivalent to that after intravenous injection. The application of a transdermal therapeutic system, prepared using the gel formulation and a microporous membrane, gave a constant plasma level of terodiline, 250–820 ng/ml, for about 48 h, indicating that the membrane-controlled systems may be an efficient drug delivery system for treatment of urinary urge incontinence.

Tolerability and steady-state pharmacokinetics of terodiline and its main metabolites in elderly patients with urinary incontinence.

The elderly form an important target group for the treatment of urinary urge incontinence with drugs such as terodiline (Mictrol, Terolin). In order to evaluate its steady-state pharmacokinetics and tolerability in geriatric patients terodiline 12.5 mg b.d. was given to 28 hospitalized patients with urinary incontinence (mean age 85 years) for six weeks. The patients were monitored during the study and for 6 weeks afterwards, blood samples being taken at regular intervals. In addition to these multi-diseased and polymedicated patients, a small, homogenous group of healthy volunteers (mean age 40 years) was studied as a reference group, being given terodiline 12.5 mg b.d. for 2 weeks. Terodiline was generally well tolerated by the patients and no significant change in blood pressure or heart rate were found. One patient was withdrawn due to adverse effects. The mean terminal half-life of terodiline was 131 h and the clearance after oral administration (clearance/systemic availability) was 39 ml.min-1. The corresponding figures for the healthy volunteers were 57 h and 75 ml.min-1. The average steady-state serum concentration was 518 micrograms.l-1 in the geriatric patients and 238 micrograms.l-1 in the healthy volunteers. Steady-state was reached within 3 weeks in 20 of the 28 patients and within 5 weeks in 7 patients. In the geriatric patients the steady-state serum concentration of the main metabolite p-hydroxyterodiline, during the last three weeks on terodiline was 45 micrograms.l-1, 57 micrograms.l-1, and 45 micrograms.l-1, respectively, and a similar value was found in the healthy volunteers, 47 micrograms.l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Dependence of the incidence of emphysema on smoking history, age, and sex

Tolterodine is a new muscarinic receptor antagonist intended for the treatment of urinary urge incontinence and other symptoms associated with an overactive bladder. The <i>in vivo</i>metabolism of ¹⁴C-labeled tolterodine was investigated in rats, mice, and dogs by analysis of blood and urine samples, whereas <i>in vitro</i> metabolism studies were performed by incubation of [¹⁴C]tolterodine with mouse, rat, dog, and human liver microsomes in the presence of NADPH. Tolterodine was extensively metabolized <i>in vivo</i>. Mice and dogs showed similar metabolite patterns, which correlated well with that observed in humans. In these species, tolterodine was metabolized along two different pathways, with the more important being the stepwise oxidation of the 5-methyl group to yield the 5-hydroxymethyl metabolite of tolterodine and then, <i>via</i> the aldehyde, the 5-carboxylic acid metabolite. The other pathway involved dealkylation of the nitrogen. In the subsequent phase II metabolism, tolterodine and the metabolites were conjugated with glucuronic acid to various degrees. Rats exhibited more extensive metabolism and a markedly different metabolite pattern, with metabolites also being formed by hydroxylation of the unsubstituted benzene ring. In addition, a gender difference was observed, with male rats showing more extensive metabolism than females. Incubation of [¹⁴C]tolterodine with liver microsomes yielded a total of five metabolites with rat liver microsomes and three with mouse, dog, and human liver microsomes. The 5-hydroxymethyl metabolite of tolterodine and <i>N</i>-dealkylated tolterodine were major metabolites in all incubations, representing 83–99% of total metabolism. Although the extent of metabolism varied among species, the metabolic profiles were similar. However, rat liver microsomes also formed metabolites hydroxylated in the unsubstituted benzene ring. These results show that the metabolism of tolterodine in mice and dogs corresponds to that observed in humans, whereas rats exhibit a different metabolite pattern.