Disease relevance of tolterodine

• Paradoxically, the most successful antagonist approved for use in urinary incontinence is the nonselective muscarinic receptor antagonist tolterodine [1].
• Interestingly, no acute urinary retention was observed and tolterodine did not affect the quality of urine flow or residual urine volume [2].
• Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia [3].
• This finding may be explained by a high placebo response and under dosage of tolterodine among children with greater body weight [4].
• RESULTS: Two patients from group 2 stopped tolterodine while 1 patient from each group stopped tamsulosin because of hypotension [2].

Psychiatry related information on tolterodine

• OBJECTIVE: To describe a 46-year-old woman who had memory loss and abnormal memory test results that improved when she discontinued tolterodine therapy [5].
• RESULTS: While taking tolterodine, the patient's score on the delayed free recall portion of the Hopkins Verbal Learning Test-Revised was at the first percentile [5].
• The age- and sex-adjusted relative risk of hallucinations on tolterodine compared with 10 drugs of other therapeutic classes, and with terodiline, another drug indicated for bladder instability, was 4.85 [95% confidence interval (CI) 2.72 to 8.66] and 1.25 (95% CI 0.62 to 2.53), respectively [6].
• Failure of tolterodine to treat clozapine-induced nocturnal enuresis [7].

High impact information on tolterodine

• The enzyme 25-hydroxylated vitamin D(3), 1 alpha-hydroxyvitamin D(3) and vitamin D(2) and also converted tolterodine, a substrate for human CYP2D6, into its 5-hydroxymethyl metabolite [8].
• The pharmacokinetics of tolterodine and 5-hydroxymethyl metabolite were determined, and the pharmacodynamic were measured [9].
• Tolterodine caused a similar decrease in salivation in both panels [9].
• CONCLUSIONS: Changes in pH affected the release of tolterodine from ER-tolterodine, while they had no effect on the release of oxybutynin from the proprietary ER technology used in ER-oxybutynin [10].
• Tolterodine is metabolised via CYP2D6 to the active metabolite 5-hydroxymethyl-tolterodine and via CYP3A to N-dealkylated metabolites [11].

Chemical compound and disease context of tolterodine

• Once-daily oxybutynin ER 10 mg was superior to tolterodine IR 4 mg/day given as two daily doses and as effective as once-daily tolterodine ER 4 mg/day in decreasing urinary incontinence; the decreases in micturition frequency with oxybutynin ER were significantly greater than those seen with either of tolterodine formulations [12].
• Comparative evaluation of central muscarinic receptor binding activity by oxybutynin, tolterodine and darifenacin used to treat overactive bladder [13].
• PURPOSE: We compare the tolerability and efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with nonneurogenic diurnal urinary incontinence and symptoms of overactive bladder [14].
• Propiverine versus tolterodine: efficacy and tolerability in patients with overactive bladder [15].
• BACKGROUND: Oxybutynin chloride and tolterodine tartrate are anticholinergic agents used to suppress involuntary bladder contractions in urinary incontinence [16].

Biological context of tolterodine

• RESULTS: No effect of food on the bioavailability of tolterodine ER capsules was apparent and there was no sign of dose-dumping with meals [17].
• Overall, the pharmacokinetics of tolterodine (irrespective of genotype) and 5-HM (extensive metabolisers only) were consistent with sustained drug release over 24 hours [18].
• OBJECTIVE: To determine whether food intake influences the pharmacokinetics of a new, once daily, extended release (ER) capsule formulation of tolterodine in healthy volunteers, and to compare its bioavailability with that of the existing immediate release (IR) tablet [17].
• The pharmacokinetics of tolterodine are dependent in large part on the pharmacogenomics of the CYP2D6 and 3A4 isozymes [11].
• Using pressure flow urodynamics, we evaluated the safety of tolterodine vs placebo in men with OAB and BOO [19].

Anatomical context of tolterodine

• Tolterodine shows functional selectivity for the bladder over the salivary glands in vivo, which is not attributable to muscarinic receptor subtype selectivity [20].
• Also, muscarinic receptor binding affinity of oxybutynin and its metabolite N-desethyl-oxybutynin in the cerebral cortex compared with that in the bladder was 2 to 3 times higher, whereas that of tolterodine and 5-hydroxymethyl metabolite was approximately 2 times lower [13].
• CONCLUSIONS: Compared with oxybutynin, tolterodine, 5-HM and DPr-P-4(N-->O) may bind more selectively to muscarinic receptors in the human bladder than in the parotid gland [21].
• CONCLUSIONS: These results suggest that at low doses tolterodine exerts an inhibitory effect on C-fiber bladder afferent nerves, thereby, improving BC during the storage phase [22].
• Tolterodine and 5-HM were 2-fold more potent for inhibiting specific [(3)H]NMS binding at cell membranes expressing the M(2) vs the M(3) subtype [21].

Associations of tolterodine with other chemical compounds

• Based upon the nonselective tolterodine, the highly M(2)-selective (R)-4-[2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl]piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M(3)-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M(3) receptors [23].
• CONCLUSION: The study demonstrates comparable efficacy, tolerability, and improvement in the quality of life of 15 mg propiverine twice-daily and 2mg tolterodine twice-daily in the treatment of the symptoms of idiopathic detrusor overactivity [15].
• METHODS: Twelve healthy male volunteers (eight extensive metabolisers [EMs] and four poor metabolisers [PMs] with respect to CYP2D6) received 4 mg tolterodine L-tartrate orally twice daily for 6 days [24].
• RESULTS: Several anticholinergic drugs are available for the treatment of OAB, including oxybutymn, tolterodine, trospium chloride, and propiverine (not available in the United States) [25].
• Effect of the proton pump inhibitor omeprazole on the pharmacokinetics of extended-release formulations of oxybutynin and tolterodine [26].

Gene context of tolterodine

• The Km for formation of N-dealkylated tolterodine by CYP3A4 was similar to that obtained in human liver microsomes and higher for CYP2C9 and -2C19 [27].
• Microsomes from cells overexpressing CYP2D6 formed 5-HM, whereas N-dealkylated tolterodine was formed by microsomes expressing CYP2C9, -2C19, and -3A4 [27].
• In addition to 25-hydroxylation, CYP2D25 also metabolizes the drug tolterodine [28].
• Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes [27].
• Biotransformation by the cytochrome P450 (CYP450) system is an important step in the activation or elimination of a large number of drugs, including oxybutynin, tolterodine, darifenacin and solifenacin, raising the possibility of clinically relevant and potentially serious drug interactions [29].

Analytical, diagnostic and therapeutic context of tolterodine

• METHODS: Sixteen male subjects (eight extensive metabolizers and eight poor metabolizers) received 4 mg tolterodine by mouth twice a day for 8 days followed by a single intravenous infusion of 1.8 mg tolterodine for 30 minutes after a washout period [9].
• No clinically relevant ECG changes have been noted with tolterodine [20].
• Oral administration of oxybutynin (76.1 micromol/kg), tolterodine (6.31 micromol/kg) and darifenacin (59.1 micromol/kg) showed binding activity that was approximately equal to that of bladder muscarinic receptors [13].
• PURPOSE: We report the results of the first 2 large randomized controlled trials designed to evaluate the efficacy and safety of tolterodine extended release in children 5 to 10 years old with symptoms of urinary urge incontinence suggestive of detrusor overactivity [4].
• Tolterodine, a competitive, nonselective antimuscarinic specifically developed for the treatment of overactive bladder, demonstrated tissue selectivity for the bladder over the parotid gland in an animal model [30].

References