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Purity: ≥98%
Tolterodine tartrate (PNU-200583E; PNU200583E; Detrol LA; Detrusitol) is a tartrate salt of tolterodine that is a potent and competitive muscarinic receptor antagonist. Tolterodines is an antimuscarinic drug that has been used for symptomatic treatment of urinary incontinence. Tolterodine acts on M2 and M3 subtypes of muscarinic receptors whereas older antimuscarinic treatments for overactive bladder act more specifically on M3 receptors. Tolterodine, although it acts on all types of receptors, has fewer side effects than oxybutynin (M3 and M1 selective, but more so in the parotid than in the bladder) as tolterodine targets the bladder more than other areas of the body.
| Targets |
M1 muscarinic receptor (Ki = 2.5 nM) [1]
- M2 muscarinic receptor (Ki = 1.7 nM) [1] - M3 muscarinic receptor (Ki = 2.0 nM) [1] - M4 muscarinic receptor (Ki = 1.4 nM) [1] - M5 muscarinic receptor (Ki = 3.7 nM) [1] |
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| ln Vitro |
Both tolterodine (IC50 14 nM) and 5-HM (IC50 5.7 nM) were found to be effective in inhibiting the contractions of the isolated guinea pig bladder caused by carbachol. The antimuscarinic potency of tolterodine was 27, 200, and 370–485, times higher, respectively, than its potency in blocking calcium channels, alpha-adrenoceptors, and histamine receptors. The IC50 values were in the microM range. Compared to bladder muscarinic receptors, the active metabolite, 5-HM, was >900 times less potent at these locations[1].
Tolterodine tartrate (Kabi-2234; PNU-200583E) (10 nM) competitively inhibited binding of [³H]N-methylscopolamine to human recombinant M1-M5 muscarinic receptors, with similar high affinity for all subtypes (Ki 1.4-3.7 nM) [1] - Incubation of isolated guinea pig bladder smooth muscle strips with Tolterodine tartrate (Kabi-2234; PNU-200583E) (0.1-100 nM) dose-dependently inhibited acetylcholine-induced contraction, with IC50 of 4.2 nM and maximum inhibition (90%) at 100 nM [1] - The 5-hydroxymethyl metabolite of Tolterodine tartrate (Kabi-2234; PNU-200583E) (10 nM) showed comparable muscarinic receptor affinity (Ki 1.2-4.5 nM) and contractile inhibition (IC50 5.1 nM) to the parent drug [1] |
| ln Vivo |
In vivo tolterodine metabolism was extensive[2]. Tolterodine at 1 or 3 mg/kg did not affect memory in the passive-avoidance test; the percentage of animals crossing and the latency to cross were similar to controls. On the other hand, scopolamine caused a memory impairment, which resulted in a reduction in the latency to cross and an increase in the quantity of animals crossing[3].
Oral administration of Tolterodine tartrate (Kabi-2234; PNU-200583E) (0.1-10 mg/kg) to mice did not affect step-through latency in the passive-avoidance response test, indicating no impairment of memory function [3] - In rats with cyclophosphamide-induced overactive bladder, oral Tolterodine tartrate (Kabi-2234; PNU-200583E) (0.3 mg/kg/day) for 7 days reduced micturition frequency by 35% and increased voided volume per micturition by 40% [1] - Intravenous injection of Tolterodine tartrate (Kabi-2234; PNU-200583E) (0.1 mg/kg) to dogs reduced bladder contractility induced by electrical stimulation of the pelvic nerve by 55% [1] |
| Enzyme Assay |
Muscarinic receptor binding assay: Membrane fractions from HEK293 cells expressing human M1-M5 receptors were prepared. Tolterodine tartrate (Kabi-2234; PNU-200583E) (0.001-100 nM) was incubated with membranes and [³H]N-methylscopolamine at 25°C for 60 minutes. Unbound ligand was removed by filtration, and bound radioactivity was quantified. Ki values were calculated via Scatchard analysis [1]
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| Cell Assay |
Bladder smooth muscle contraction assay: Isolated guinea pig bladder smooth muscle strips were mounted in oxygenated Krebs-Ringer solution. Strips were precontracted with acetylcholine (1 μM), then treated with Tolterodine tartrate (Kabi-2234; PNU-200583E) (0.1-100 nM). Contraction tension was recorded, and IC50 values were derived from dose-response inhibition curves [1]
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| Animal Protocol |
1 mg/kg, i.v.
Cat Passive-avoidance memory test model: Male NMRI mice (8 weeks old) received Tolterodine tartrate (Kabi-2234; PNU-200583E) (0.1-10 mg/kg) dissolved in distilled water via oral gavage 60 minutes before training and 30 minutes before retention testing in the passive-avoidance apparatus. Step-through latency was recorded to assess memory function [3] - Overactive bladder rat model: Male Wistar rats (10 weeks old) were injected with cyclophosphamide (150 mg/kg, ip) to induce overactive bladder. Three days post-injection, rats were treated with Tolterodine tartrate (Kabi-2234; PNU-200583E) (0.3 mg/kg/day, po) for 7 days. Micturition parameters were measured via metabolic cage analysis [1] - Canine bladder contractility model: Adult beagle dogs (n=4) were anesthetized, and the bladder was catheterized. Tolterodine tartrate (Kabi-2234; PNU-200583E) (0.1 mg/kg) was administered intravenously, and bladder contractions were induced by electrical stimulation of the pelvic nerve. Contraction amplitude was recorded for 2 hours [1] |
| ADME/Pharmacokinetics |
Tolterodine tartrate (Kabi-2234; PNU-200583E) is rapidly absorbed after oral administration, with an oral bioavailability of 77% in humans [2]
-The drug is metabolized in the liver by cytochrome P450 2D6 (CYP2D6) to the active metabolite 5-hydroxymethyl metabolite, and by CYP3A4 to the inactive metabolite [2] -The elimination half-life (t1/2) of the fast metabolizer of CYP2D6 is 2-3 hours, and the elimination half-life of the slow metabolizer of CYP2D6 is 10-17 hours [2] -In mice, rats and dogs, 60-80% of the administered dose is excreted in the urine within 24 hours (10-20% is the original drug and 30-40% is the active metabolite) [2] |
| Toxicity/Toxicokinetics |
In clinical use, tolterodine tartrate (Kabi-2234; PNU-200583E) (1–4 mg/day, orally) has been associated with mild anticholinergic adverse reactions, including dry mouth (23%), constipation (8%), and blurred vision (5%); no serious hepatotoxicity/nephrotoxicity has been reported [1]. - Tolterodine tartrate (Kabi-2234; PNU-200583E) has a plasma protein binding rate of 96% in human plasma [1]. - The acute oral LD50 of tolterodine tartrate (Kabi-2234; PNU-200583E) is 138 mg/kg in mice, 265 mg/kg in rats, and >50 mg/kg in dogs [1]. - At therapeutic doses, no significant drug interactions with CYP2D6 or CYP3A4 substrates/inhibitors have been observed [2].
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| References |
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| Additional Infomation |
Tolterodine tartrate is the tartrate salt form of tolterodine, a diphenylmethyl compound belonging to the muscarinic receptor antagonist class, possessing antimuscarinic and antispasmodic effects. Tolterodine and its active metabolite, 5-hydroxymethyltolterodine, competitively block muscarinic receptors, thereby inhibiting the binding of acetylcholine receptors. This antagonistic effect leads to increased residual urine volume, reflecting incomplete bladder emptying, and reduces detrusor pressure, indicating its antimuscarinic effect on the lower urinary tract. The 5-hydroxymethyl metabolite appears to contribute significantly to the therapeutic effect.
An antimuscarinic drug that selectively acts on bladder muscarinic receptors, used to treat urinary incontinence and urge incontinence. See also: Tolterodine (with active fraction). Tolterodine tartrate (Kabi-2234; PNU-200583E) is a non-selective competitive muscarinic receptor antagonist with similar affinity for the M1-M5 subtypes[1]. - The clinically approved indication is overactive bladder, for the improvement of symptoms. By blocking muscarinic receptors and inhibiting bladder smooth muscle contraction, it improves symptoms such as urinary frequency, urgency, nocturia, and urge incontinence[1]. - Its active metabolites help to exert therapeutic effects, especially in patients with weak CYP2D6 metabolism, ensuring consistency of efficacy among different patient groups[2]. - Unlike some anticholinergic drugs, tolterodine tartrate (Kabi-2234; PNU-200583E) does not impair memory function in animal models, indicating good central nervous system safety[3]. |
| Molecular Formula |
C22H31NO.C4H6O6
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| Molecular Weight |
475.57
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| Exact Mass |
475.256
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| CAS # |
124937-52-6
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| Related CAS # |
Tolterodine;124937-51-5
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| PubChem CID |
443878
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| Appearance |
White to off-white solid powder
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| Density |
1.003 g/cm3
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| Boiling Point |
442.2ºC at 760 mmHg
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| Melting Point |
205-210ºC
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| Flash Point |
192.1ºC
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| Vapour Pressure |
1.97E-08mmHg at 25°C
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| LogP |
3.218
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
34
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| Complexity |
474
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| Defined Atom Stereocenter Count |
3
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| SMILES |
CC1=CC(=C(C=C1)O)[C@H](CCN(C(C)C)C(C)C)C2=CC=CC=C2.[C@@H]([C@H](C(=O)O)O)(C(=O)O)O
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| InChi Key |
TWHNMSJGYKMTRB-KXYUELECSA-N
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| InChi Code |
InChI=1S/C22H31NO.C4H6O6/c1-16(2)23(17(3)4)14-13-20(19-9-7-6-8-10-19)21-15-18(5)11-12-22(21)24;5-1(3(7)8)2(6)4(9)10/h6-12,15-17,20,24H,13-14H2,1-5H3;1-2,5-6H,(H,7,8)(H,9,10)/t20-;1-,2-/m11/s1
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| Chemical Name |
(R)-2-(3-(diisopropylamino)-1-phenylpropyl)-4-methylphenol (2R,3R)-2,3-dihydroxysuccinate
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.26 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.26 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1027 mL | 10.5137 mL | 21.0274 mL | |
| 5 mM | 0.4205 mL | 2.1027 mL | 4.2055 mL | |
| 10 mM | 0.2103 mL | 1.0514 mL | 2.1027 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01488578 | Completed Has Results | Drug: Tolterodine tartrate | Overactive Bladder | Pfizer's Upjohn has merged with Mylan to form Viatris Inc. |
December 2006 | |
| NCT00768521 | Completed Has Results | Drug: tolterodine tartrate Drug: Comparator: Placebo to tolterodine tartrate |
Overactive Bladder | Merck Sharp & Dohme LLC | September 3, 2008 | Phase 1 |
| NCT02723279 | Completed | Behavioral: EPNS Drug: TT |
Urgency-frequency Syndrome | Shanghai Institute of Acupuncture, Moxibustion and Meridian | April 2016 | Not Applicable |
| NCT00939120 | Completed Has Results | Drug: Tolterodine ER 4mg Drug: Placebo Drug: Pre-randomization Dutasteride |
Benign Prostatic Hyperplasia (BPH) | Siami, Paul F., M.D. | July 2009 | Phase 4 |
| NCT05250245 | Completed | Drug: Tolterodine Tartrate 4 MG Other: Continuous positive airway pressure therapy (CPAP) |
Overactive Bladder Obstructive Sleep Apnea Overactive Bladder Syndrome |
Yuzuncu Yıl University | June 1, 2020 | Phase 4 |
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