Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C22H31NO.C4H4O4 |
| Molecular Weight | 441.5598 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 1 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
OC(=O)\C=C\C(O)=O.CC(C)N(CC[C@H](C1=CC=CC=C1)C2=C(O)C=CC(C)=C2)C(C)C
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
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.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL245 |
|||
Target ID: CHEMBL211 |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | DETROL Approved UseTolterodine 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 Date1998 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
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
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
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
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
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
| Dose | Population | Adverse 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%) Sources: Page: p.11Dizziness (common) Headache (common) |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| 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
| Title | Date | PubMed |
|---|---|---|
| Safety profile of tolterodine as used in general practice in England: results of prescription-event monitoring. | 2001 |
|
| Costs and resources associated with the treatment of overactive bladder using retrospective medical care claims data. | 2001 Aug |
|
| Pharmacological characterization of muscarinic receptors in mouse isolated urinary bladder smooth muscle. | 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 |
|
| Urinary incontinence management: new questions from old assumptions. | 2001 Jun |
|
| Tolterodine: a safe and effective treatment for older patients with overactive bladder. | 2001 Jun |
|
| Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. | 2001 Jun |
|
| Clarification--Drug risk in patients with glaucoma. | 2001 Jun 11 |
|
| Which muscarinic receptor is important in the bladder? | 2001 Nov |
|
| Tolterodine once-daily in treatment of the overactive bladder. | 2001 Nov |
|
| Medical treatment of overactive 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 |
|
| Tolterodine: a clinical review. | 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 |
|
| Tolterodine reduces the number of urge incontinence episodes in patients with an overactive bladder. | 2001 Sep |
|
| Effect of tolterodine on the anticoagulant actions and pharmacokinetics of single-dose warfarin in healthy volunteers. | 2002 |
|
| Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET). | 2002 |
|
| Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. | 2002 |
|
| Long-term health-related quality of life of patients receiving extended-release tolterodine for overactive bladder. | 2002 Dec |
|
| Health-related quality of life of patients receiving extended-release tolterodine for overactive bladder. | 2002 Dec |
|
| 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 |
|
| Comparison of laparoscopic Burch and tension-free vaginal tape in treating stress urinary incontinence in obese patients. | 2002 Jan-Mar |
|
| Current pharmacotherapeutic strategies for overactive bladder. | 2002 Jul |
|
| Gateways to clinical trials. | 2002 Jul-Aug |
|
| 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 |
|
| 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 |
|
| Tolterodine-associated acute mixed liver injury. | 2002 May |
|
| Functional role of central muscarinic receptors for micturition in normal conscious rats. | 2002 Nov |
|
| Different responses to drugs against overactive bladder in detrusor muscle of pig, guinea pig and mouse. | 2002 Nov 1 |
|
| The newer antimuscarinic drugs: bladder control with less dry mouth. | 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 |
|
| New treatment options for overactive bladder and incontinence. | 2002 Summer |
|
| Effects of ATP-sensitive K+ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction. | 2003 |
|
| 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 |
|
| Therapeutic efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with diurnal urinary incontinence. | 2003 Jan |
|
| The use of tolterodine in children after oxybutynin failure. | 2003 Mar |
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
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.
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300000025701
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25119183
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615254-93-8
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HH7RXJ4PW1
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ACTIVE MOIETY
SUBSTANCE RECORD
