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
Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine.	2001	11327200
Treatment of overactive bladder: long-term tolerability and efficacy of tolterodine.	2001 Apr	11374317
Tissue distribution of tolterodine, a muscarinic receptor antagonist, and transfer into fetus and milk in mice.	2001 Feb	11258042
Pharmacological characterization of muscarinic receptors in dog isolated ciliary and urinary bladder smooth muscle.	2001 Feb	11181424
Tolterodine versus oxybutynin in the treatment of urge urinary incontinence: a meta-analysis.	2001 Jul	11483904
Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system.	2001 Jun	11402632
Overactive bladder: optimizing quality of care.	2001 Mar	11261408
A comparison of the effects on saliva output of oxybutynin chloride and tolterodine tartrate.	2001 May	11394733
Which muscarinic receptor is important in the bladder?	2001 Nov	11760777
Evidence for the efficacy and safety of tolterodine in the treatment of overactive bladder.	2001 Oct	11825311
The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro.	2001 Oct-Dec	12123469
[Continence problems after radical prostatectomy: medical treatment].	2001 Sep	11822060
Gateways to Clinical Trials.	2002 Apr	12087878
Tolterodine: a safe and effective treatment for older patients with overactive bladder.	2002 Apr	11982685
Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: a review.	2002 Jan	11999467
Risk of delirium with concomitant use of tolterodine and acetylcholinesterase inhibitors.	2002 Jun	12110086
Achieving bladder control. Treatment in the primary care setting.	2002 May	12420535
Tolterodine: as effective but better tolerated than oxybutynin in Asian patients with symptoms of overactive bladder.	2002 May	12060436
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
The newer antimuscarinic drugs: bladder control with less dry mouth.	2002 Oct	12371799
Gateways to Clinical Trials.	2002 Sep	12428432
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

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