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Details

Stereochemistry ABSOLUTE
Molecular Formula C22H31NO.C4H4O4
Molecular Weight 441.5608
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of TOLTERODINE FUMARATE

SMILES

CC(C)N(CC[C@]([H])(c1ccccc1)c2cc(C)ccc2O)C(C)C.C(\[H])(=C(/[H])\C(=O)O)/C(=O)O

InChI

InChIKey=HKTZTYRSKPLEIQ-BOQYJDHWSA-N
InChI=1S/C22H31NO.C4H4O4/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;5-3(6)1-2-4(7)8/h6-12,15-17,20,24H,13-14H2,1-5H3;1-2H,(H,5,6)(H,7,8)/b;2-1+/t20-;/m1./s1

HIDE SMILES / InChI

Molecular Formula C4H4O4
Molecular Weight 116.0723
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Molecular Formula C22H31NO
Molecular Weight 325.4885
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Tolterodine is competitive muscarinic receptors M3 and M2 antagonist. It was sold under trade names detrol for the treatment of overactive bladder with symptoms of urge urinary incontinence. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity and affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels. Tolterodine has a pronounced effect on bladder function. The main effects of tolterodine at 1 and 5 hours were an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure. These findings are consistent with an antimuscarinic action on the lower urinary tract.

CNS Activity

Curator's Comment:: Both oxybutynin and tolterodine are tertiary amines that cross the blood-brain barrier. However, tolterodine is 30 times less lipophilic than oxybutynin.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
DETROL

Approved Use

Tolterodine tartrate extended-release capsules are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency [see CLINICAL STUDIES (14)

Launch Date

8.9078399E11
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1.8 μg/L
8 mg single, oral
dose: 8 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: HIGH-FAT
2.3 μg/L
8 mg single, oral
dose: 8 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: FASTED
1.6 μg/L
4 mg single, oral
dose: 4 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
10 μg/L
4 mg single, oral
dose: 4 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
19 μg/L
4 mg 2 times / day multiple, oral
dose: 4 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
2.6 μg/L
4 mg 2 times / day multiple, oral
dose: 4 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
23 μg × h/L
8 mg single, oral
dose: 8 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: HIGH-FAT
27 μg × h/L
8 mg single, oral
dose: 8 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
8.1 h
8 mg single, oral
dose: 8 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: HIGH-FAT
7.9 h
8 mg single, oral
dose: 8 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: FASTED
2 h
4 mg single, oral
dose: 4 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
6.5 h
4 mg single, oral
dose: 4 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
9.6 h
4 mg 2 times / day multiple, oral
dose: 4 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
2.2 h
4 mg 2 times / day multiple, oral
dose: 4 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TOLTERODINE plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
2 mg 2 times / day multiple, oral
Recommended
Dose: 2 mg, 2 times / day
Route: oral
Route: multiple
Dose: 2 mg, 2 times / day
Sources: Page: p.804
unhealthy, 20-93
n = 507
Health Status: unhealthy
Condition: Overactive bladder
Age Group: 20-93
Sex: M+F
Population Size: 507
Sources: Page: p.804
Disc. AE: Dry mouth...
AEs leading to
discontinuation/dose reduction:
Dry mouth (2.4%)
Sources: Page: p.804
4 mg 2 times / day multiple, oral
Highest studied dose
Dose: 4 mg, 2 times / day
Route: oral
Route: multiple
Dose: 4 mg, 2 times / day
Sources: Page: p.997
unhealthy, 52
n = 58
Health Status: unhealthy
Condition: Overactive bladder
Age Group: 52
Sex: M+F
Population Size: 58
Sources: Page: p.997
Disc. AE: Urinary retention...
AEs leading to
discontinuation/dose reduction:
Urinary retention (6.9%)
Sources: Page: p.997
2 mg 2 times / day multiple, oral
Recommended
Dose: 2 mg, 2 times / day
Route: oral
Route: multiple
Dose: 2 mg, 2 times / day
Sources: Page: p.11
unhealthy
n = 986
Health Status: unhealthy
Condition: Overactive bladder
Sex: M+F
Population Size: 986
Sources: Page: p.11
Disc. AE: Dry mouth, Dizziness...
AEs leading to
discontinuation/dose reduction:
Dry mouth (1%)
Dizziness (common)
Headache (common)
Sources: Page: p.11
AEs

AEs

AESignificanceDosePopulation
Dry mouth 2.4%
Disc. AE
2 mg 2 times / day multiple, oral
Recommended
Dose: 2 mg, 2 times / day
Route: oral
Route: multiple
Dose: 2 mg, 2 times / day
Sources: Page: p.804
unhealthy, 20-93
n = 507
Health Status: unhealthy
Condition: Overactive bladder
Age Group: 20-93
Sex: M+F
Population Size: 507
Sources: Page: p.804
Urinary retention 6.9%
Disc. AE
4 mg 2 times / day multiple, oral
Highest studied dose
Dose: 4 mg, 2 times / day
Route: oral
Route: multiple
Dose: 4 mg, 2 times / day
Sources: Page: p.997
unhealthy, 52
n = 58
Health Status: unhealthy
Condition: Overactive bladder
Age Group: 52
Sex: M+F
Population Size: 58
Sources: Page: p.997
Dry mouth 1%
Disc. AE
2 mg 2 times / day multiple, oral
Recommended
Dose: 2 mg, 2 times / day
Route: oral
Route: multiple
Dose: 2 mg, 2 times / day
Sources: Page: p.11
unhealthy
n = 986
Health Status: unhealthy
Condition: Overactive bladder
Sex: M+F
Population Size: 986
Sources: Page: p.11
Dizziness common
Disc. AE
2 mg 2 times / day multiple, oral
Recommended
Dose: 2 mg, 2 times / day
Route: oral
Route: multiple
Dose: 2 mg, 2 times / day
Sources: Page: p.11
unhealthy
n = 986
Health Status: unhealthy
Condition: Overactive bladder
Sex: M+F
Population Size: 986
Sources: Page: p.11
Headache common
Disc. AE
2 mg 2 times / day multiple, oral
Recommended
Dose: 2 mg, 2 times / day
Route: oral
Route: multiple
Dose: 2 mg, 2 times / day
Sources: Page: p.11
unhealthy
n = 986
Health Status: unhealthy
Condition: Overactive bladder
Sex: M+F
Population Size: 986
Sources: Page: p.11
PubMed

PubMed

TitleDatePubMed
Safety profile of tolterodine as used in general practice in England: results of prescription-event monitoring.
2001
Twelve-month treatment of overactive bladder: efficacy and tolerability of tolterodine.
2001
Therapeutic opportunities from muscarinic receptor research.
2001 Aug
Cost-Effectiveness of tolterodine for patients with urge incontinence who discontinue initial therapy with oxybutynin: a Canadian perspective.
2001 Dec
Is tolterodine (Detrol) or oxybutynin (Ditropan) the best for treatment of urge urinary incontinence?
2001 Dec
Is extended-release oxybutynin (Ditropan XL) or tolterodine (Detrol) more effective in the treatment of an overactive bladder?
2001 Jul
Tolterodine versus oxybutynin in the treatment of urge urinary incontinence: a meta-analysis.
2001 Jul
Failure of tolterodine to treat clozapine-induced nocturnal enuresis.
2001 Jul-Aug
Urinary incontinence management: new questions from old assumptions.
2001 Jun
Tolterodine: a safe and effective treatment for older patients with overactive bladder.
2001 Jun
Tolterodine: an overview.
2001 Nov
Which muscarinic receptor is important in the bladder?
2001 Nov
The importance of residues in substrate recognition site 3 for the catalytic function of CYP2D25 (vitamin D 25-hydroxylase).
2001 Nov 9
Evidence for the efficacy and safety of tolterodine in the treatment of overactive bladder.
2001 Oct
POEMS (patient-oriented evidence that matters) spark discussion.
2001 Oct
The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro.
2001 Oct-Dec
[Continence problems after radical prostatectomy: medical treatment].
2001 Sep
Anticholinergic drugs versus placebo for overactive bladder syndrome in adults.
2002
Gateways to Clinical Trials.
2002 Apr
Methodologic shortcomings inherent in a post-hoc analysis.
2002 Dec
Medication update.
2002 Feb
Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: a review.
2002 Jan
Gateways to clinical trials.
2002 Jan-Feb
Current pharmacotherapeutic strategies for overactive bladder.
2002 Jul
Risk of delirium with concomitant use of tolterodine and acetylcholinesterase inhibitors.
2002 Jun
Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder.
2002 Jun
Effect of muscarinic antagonists on micturition pressure measured by cystometry in normal, conscious rats.
2002 Jun
Efficacy of botulinum-a toxin in children with detrusor hyperreflexia due to myelomeningocele: preliminary results.
2002 Mar
Pharmacotherapy of the overactive bladder and advances in drug delivery.
2002 Mar
Muscarinic receptor antagonist-induced lenticular opacity in rats.
2002 Mar
Tolterodine and its active 5-hydroxymethyl metabolite: pure muscarinic receptor antagonists.
2002 May
Tolterodine: as effective but better tolerated than oxybutynin in Asian patients with symptoms of overactive bladder.
2002 May
Efficacy, safety, and tolerability of extended-release once-daily tolterodine treatment for overactive bladder in older versus younger patients.
2002 May
Tolterodine-associated acute mixed liver injury.
2002 May
Assessment and conservative management of the neuropathic bladder.
2002 May
Overactive bladder patients and role of the pharmacist.
2002 May-Jun
Human variability in polymorphic CYP2D6 metabolism: is the kinetic default uncertainty factor adequate?
2002 Nov
The newer antimuscarinic drugs: bladder control with less dry mouth.
2002 Oct
Pharmacologic treatment for detrusor overactivity.
2002 Oct
Gateways to Clinical Trials.
2002 Sep
Does gender or age affect the efficacy and safety of tolterodine?
2002 Sep
A randomized controlled trial of tolterodine and oxybutynin on tolerability and clinical efficacy for treating Chinese women with an overactive bladder.
2002 Sep
Characterization of a new muscarinic receptor antagonist PNU-171990 in guinea pig, cat and human smooth muscle.
2002 Sep 13
Treatment can lead to a long dry spell.
2002 Spring
New treatment options for overactive bladder and incontinence.
2002 Summer
25-Hydroxylation of vitamin D3 in primary cultures of pig hepatocytes: evidence for a role of both CYP2D25 and CYP27A1.
2003 Apr 11
A new once-daily formulation of tolterodine provides superior efficacy and is well tolerated in women with overactive bladder.
2003 Feb
In vivo evaluation of the potency and bladder-vascular selectivity of the ATP-sensitive potassium channel openers (-)-cromakalim, ZD6169 and WAY-133537 in rats.
2003 Feb
Simplified bladder training augments the effectiveness of tolterodine in patients with an overactive bladder.
2003 Jan
The use of tolterodine in children after oxybutynin failure.
2003 Mar
Patents

Sample Use Guides

The initial recommended dose of DETROL (tolterodine tartrate tablets) is 2 mg twice daily. The dose may be lowered to 1 mg twice daily based on individual response and tolerability. For patients with significantly reduced hepatic or renal function or who are currently taking drugs that are potent inhibitors of CYP3A4, the recommended dose of DETROL is 1 mg twice daily
Route of Administration: Oral
In Vitro Use Guide
It was compared 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. 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). 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.
Substance Class Chemical
Created
by admin
on Sat Jun 26 11:53:14 UTC 2021
Edited
by admin
on Sat Jun 26 11:53:14 UTC 2021
Record UNII
HH7RXJ4PW1
Record Status Validated (UNII)
Record Version
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Name Type Language
TOLTERODINE FUMARATE
Common Name English
PHENOL, 2-((1R)-3-(BIS(1-METHYLETHYL)AMINO)-1-PHENYLPROPYL)-4-METHYL-, (2E)-2-BUTENEDIOATE (1:1) (SALT)
Common Name English
TOLTERODINE FUMARATE [WHO-DD]
Common Name English
Code System Code Type Description
PUBCHEM
25119183
Created by admin on Sat Jun 26 11:53:14 UTC 2021 , Edited by admin on Sat Jun 26 11:53:14 UTC 2021
PRIMARY
CAS
615254-93-8
Created by admin on Sat Jun 26 11:53:14 UTC 2021 , Edited by admin on Sat Jun 26 11:53:14 UTC 2021
PRIMARY
FDA UNII
HH7RXJ4PW1
Created by admin on Sat Jun 26 11:53:14 UTC 2021 , Edited by admin on Sat Jun 26 11:53:14 UTC 2021
PRIMARY
Related Record Type Details
PARENT -> SALT/SOLVATE
Related Record Type Details
ACTIVE MOIETY