TOLTERODINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H31NO
Molecular Weight	325.4876
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)N(CC[C@H](C1=CC=CC=C1)C2=C(O)C=CC(C)=C2)C(C)C

InChI

InChIKey=OOGJQPCLVADCPB-HXUWFJFHSA-N

InChI=1S/C22H31NO/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/h6-12,15-17,20,24H,13-14H2,1-5H3/t20-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/16465186

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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Muscarinic acetylcholine receptor M3 159 Target ID: CHEMBL245 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16465186	Antagonist 2778
Muscarinic acetylcholine receptor M2 121 Target ID: CHEMBL211 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16465186	Antagonist 2778

Conditions

Condition	Modality	Targets	Highest Phase	Product
Overactive bladder 38 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf	Primary		Approved 8429	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 1998

C_max

Value	Dose	Analyte	Population
1.8 μg/L OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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

T_1/2

Value	Dose	Analyte	Population
8.1 h OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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 OTHER GOV https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-228_Detrol%20LA_BioPharmr.pdf	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: https://pubmed.ncbi.nlm.nih.gov/12028164 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: https://pubmed.ncbi.nlm.nih.gov/12028164 Page: p.804	Disc. AE: Dry mouth... AEs leading to discontinuation/dose reduction: Dry mouth (2.4%) Sources: https://pubmed.ncbi.nlm.nih.gov/12028164 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: https://pubmed.ncbi.nlm.nih.gov/10223495 Page: p.997	unhealthy, 52 n = 58 Health Status: unhealthy Condition: Overactive bladder Age Group: 52 Sex: M+F Population Size: 58 Sources: https://pubmed.ncbi.nlm.nih.gov/10223495 Page: p.997	Disc. AE: Urinary retention... AEs leading to discontinuation/dose reduction: Urinary retention (6.9%) Sources: https://pubmed.ncbi.nlm.nih.gov/10223495 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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf Page: p.11	unhealthy n = 986 Health Status: unhealthy Condition: Overactive bladder Sex: M+F Population Size: 986 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf Page: p.11	Disc. AE: Dry mouth, Dizziness... AEs leading to discontinuation/dose reduction: Dry mouth (1%) Dizziness (common) Headache (common) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf Page: p.11

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: https://pubmed.ncbi.nlm.nih.gov/12028164 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: https://pubmed.ncbi.nlm.nih.gov/12028164 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: https://pubmed.ncbi.nlm.nih.gov/10223495 Page: p.997	unhealthy, 52 n = 58 Health Status: unhealthy Condition: Overactive bladder Age Group: 52 Sex: M+F Population Size: 58 Sources: https://pubmed.ncbi.nlm.nih.gov/10223495 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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf Page: p.11	unhealthy n = 986 Health Status: unhealthy Condition: Overactive bladder Sex: M+F Population Size: 986 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf 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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf Page: p.11	unhealthy n = 986 Health Status: unhealthy Condition: Overactive bladder Sex: M+F Population Size: 986 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf 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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf Page: p.11	unhealthy n = 986 Health Status: unhealthy Condition: Overactive bladder Sex: M+F Population Size: 986 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020771s022lbl.pdf Page: p.11

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:9622	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9622
ChemicalBook	CB1128442	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1128442
ChemicalBook	CB4128443	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4128443
MolPort	MolPort-002-885-868	https://www.molport.com/shop/molecule-link/MolPort-002-885-868
ZINC	ZINC000000968336	http://zinc15.docking.org/substances/ZINC000000968336
eMolecules	29542663	https://www.emolecules.com/cgi-bin/more?vid=29542663
eMolecules	902595	https://www.emolecules.com/cgi-bin/more?vid=902595

PubMed

Title	Date	PubMed
The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro.	2001 Oct-Dec	12123469
Effect of tolterodine on the anticoagulant actions and pharmacokinetics of single-dose warfarin in healthy volunteers.	2002	12572529
Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET).	2002	12201616
Anticholinergic drugs versus placebo for overactive bladder syndrome in adults.	2002	12137711
Tolterodine: selectivity for the urinary bladder over the eye (as measured by visual accommodation) in healthy volunteers.	2002	12001821
Gateways to Clinical Trials.	2002 Apr	12087878
A multicenter, prospective, open-label study of tolterodine extended-release 4 mg for overactive bladder: the speed of onset of therapeutic assessment trial (STAT).	2002 Apr	12017406
Tolterodine: a safe and effective treatment for older patients with overactive bladder.	2002 Apr	11982685
Long-term health-related quality of life of patients receiving extended-release tolterodine for overactive bladder.	2002 Dec	12516956
Health-related quality of life of patients receiving extended-release tolterodine for overactive bladder.	2002 Dec	12516955
Advances in drug delivery: improved bioavailability and drug effect.	2002 Dec	12425864
Methodologic shortcomings inherent in a post-hoc analysis.	2002 Dec	12425862
Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: a review.	2002 Jan	11999467
Gateways to clinical trials.	2002 Jan-Feb	11980386
Comparison of laparoscopic Burch and tension-free vaginal tape in treating stress urinary incontinence in obese patients.	2002 Jan-Mar	12002291
Current pharmacotherapeutic strategies for overactive bladder.	2002 Jul	12083983
Gateways to clinical trials.	2002 Jul-Aug	12224444
The overactive bladder: a nursing perspective.	2002 Jun	12394076
Risk of delirium with concomitant use of tolterodine and acetylcholinesterase inhibitors.	2002 Jun	12110086
Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder.	2002 Jun	12074774
Effect of muscarinic antagonists on micturition pressure measured by cystometry in normal, conscious rats.	2002 Jun	12031395
Achieving bladder control. Treatment in the primary care setting.	2002 May	12420535
Tolterodine and its active 5-hydroxymethyl metabolite: pure muscarinic receptor antagonists.	2002 May	12076307
Tolterodine: as effective but better tolerated than oxybutynin in Asian patients with symptoms of overactive bladder.	2002 May	12060436
Efficacy, safety, and tolerability of extended-release once-daily tolterodine treatment for overactive bladder in older versus younger patients.	2002 May	12028164
Tolterodine-associated acute mixed liver injury.	2002 May	11978158
Assessment and conservative management of the neuropathic bladder.	2002 May	11973763
Overactive bladder patients and role of the pharmacist.	2002 May-Jun	12030634
Muscarinic receptor subtypes and management of the overactive bladder.	2002 Nov	12493364
Conservative management in neurogenic bladder dysfunction.	2002 Nov	12409875
Functional role of central muscarinic receptors for micturition in normal conscious rats.	2002 Nov	12394771
Human variability in polymorphic CYP2D6 metabolism: is the kinetic default uncertainty factor adequate?	2002 Nov	12176090
Different responses to drugs against overactive bladder in detrusor muscle of pig, guinea pig and mouse.	2002 Nov 1	12409006
The newer antimuscarinic drugs: bladder control with less dry mouth.	2002 Oct	12371799
Pharmacologic treatment for detrusor overactivity.	2002 Oct	12354344
Treatment of overactive bladder: the Antimuscarinic Clinical Effectiveness Trial.	2002 Oct	12354340
The subtypes of muscarinic receptors for neurogenic bladder contraction in rats.	2002 Oct 4	12354576
Gateways to Clinical Trials.	2002 Sep	12428432
Does gender or age affect the efficacy and safety of tolterodine?	2002 Sep	12187215
A randomized controlled trial of tolterodine and oxybutynin on tolerability and clinical efficacy for treating Chinese women with an overactive bladder.	2002 Sep	12175392
Characterization of a new muscarinic receptor antagonist PNU-171990 in guinea pig, cat and human smooth muscle.	2002 Sep 13	12231388
Treatment can lead to a long dry spell.	2002 Spring	11974567
New treatment options for overactive bladder and incontinence.	2002 Summer	12116753
Effects of ATP-sensitive K+ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction.	2003	12579633
25-Hydroxylation of vitamin D3 in primary cultures of pig hepatocytes: evidence for a role of both CYP2D25 and CYP27A1.	2003 Apr 11	12670492
A new once-daily formulation of tolterodine provides superior efficacy and is well tolerated in women with overactive bladder.	2003 Feb	12601517
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	12581020
Simplified bladder training augments the effectiveness of tolterodine in patients with an overactive bladder.	2003 Jan	12614251
Therapeutic efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with diurnal urinary incontinence.	2003 Jan	12478180
The use of tolterodine in children after oxybutynin failure.	2003 Mar	12603422

Patents

Sample Use Guides

In Vivo Use Guide

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.

Name

Type

Language

TOLTERODINE

Official Name

English

Tolterodine [WHO-DD]

Common Name

English

TOLTERODINE [USAN]

Common Name

English

TOLTERODINE [VANDF]

Common Name

English

KABI-2234

Code

English

TOLTERODINE [MI]

Common Name

English

tolterodine [INN]

Common Name

English

KABI 2234

Code

English

Classification Tree Code System Code

NDF-RT

N0000000125