Identification

Name
Propiverine
Accession Number
DB12278
Type
Small Molecule
Groups
Approved, Investigational
Description

Propiverine is a widely used antimuscarinic drug with a mixed mode of action in the treatment of symptoms associated with overactive bladder (OAB) [1].

Overactive bladder (OAB) is a chronic condition of the lower urinary tract characterized by urinary urgency, increased frequency of urination, and nocturia (frequent waking during the night to urinate). OAB has a negative impact on quality of life and may lead to leakage and inconvenient urinary accidents [15], [16]. Overactive bladder syndrome affects millions of elderly individuals in the United States and shows equal prevalence in men and women. The impact of OAB on quality of life is sometimes devastating, especially to elderly patients with other medical conditions [16].

Propiverine hydrochloride is a bladder detrusor muscle relaxant drug with dual antimuscarinic and calcium-modulating properties for the treatment of OAB [7].

Structure
Thumb
Synonyms
  • Propiverina
Product Ingredients
IngredientUNIICASInChI Key
Propiverine hydrochlorideDC4GZD10H354556-98-8KFUJMHHNLGCTIJ-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MictorylCapsule, extended release30 mgOralDuchesnay Inc.2017-05-08Not applicableCanada
MictorylCapsule, extended release45 mgOralDuchesnay Inc.2017-05-08Not applicableCanada
Mictoryl PediatricTablet5 mgOralDuchesnay Inc.2017-04-13Not applicableCanada
Categories
UNII
468GE2241L
CAS number
60569-19-9
Weight
Average: 367.4813
Monoisotopic: 367.214743799
Chemical Formula
C23H29NO3
InChI Key
QPCVHQBVMYCJOM-UHFFFAOYSA-N
InChI
InChI=1S/C23H29NO3/c1-3-18-26-23(19-10-6-4-7-11-19,20-12-8-5-9-13-20)22(25)27-21-14-16-24(2)17-15-21/h4-13,21H,3,14-18H2,1-2H3
IUPAC Name
1-methylpiperidin-4-yl 2,2-diphenyl-2-propoxyacetate
SMILES
CCCOC(C(=O)OC1CCN(C)CC1)(C1=CC=CC=C1)C1=CC=CC=C1

Pharmacology

Indication

Indicated for symptomatic treatment of urinary incontinence and/or increased urinary frequency and urgency in patients with overactive bladder (OAB) [6]. Propiverine may also be used in patients with neurogenic bladder as a result of spinal cord injury [5].

Associated Conditions
Pharmacodynamics

Propiverine hydrochloride inhibits abnormal contractions of bladder smooth muscle in vivo through not only its anticholinergic activity but also its concurrent calcium antagonistic activity [8]. Through the above-mentioned mechanism, propiverine is able to relieve the symptoms of overactive bladder.

In animal models, this administration of this drug leads to a dose-dependent decrease in intravesical pressure of the bladder and an increase in bladder capacity [6]. In patients with symptoms of OAB resulting from idiopathic detrusor muscle overactivity (IDO) or neurogenic detrusor overactivity (NDO), propiverine showed dose-dependent efficacy and tolerability [1].

Mechanism of action

Propiverine demonstrates both anticholinergic and calcium-modulating properties. The efferent connection of the pelvic nerve is inhibited due to the anticholinergic action exerted by this drug, leading to relaxation of bladder smooth muscle. Propiverine blocks calcium ion influx and modulates the intracellular calcium in urinary bladder smooth muscle cells, resulting in the inhibition of muscle spasm [6]. The bladder contains several muscarinic receptors. Acetylcholine is the main contractile neurotransmitter in the human bladder detrusor muscle, and antimuscarinics such as propiverine exert their effects by competitively inhibiting the binding of acetylcholine at muscarinic receptors on detrusor smooth muscle cells and other structures within the bladder wall [17]. In one study, After oral treatment with propiverine, the bladder showed the highest concentration of M-2, indicating a targeted distribution of this metabolite into the bladder. Therefore, muscarinic receptor-2 may highly contribute to the relatively selective and long-lasting occupation of bladder muscarinic receptors after oral ingestion of propiverine [19].

TargetActionsOrganism
AMuscarinic acetylcholine receptor M1
antagonist
Human
AMuscarinic acetylcholine receptor M2
antagonist
Human
AMuscarinic acetylcholine receptor M3
antagonist
Human
UMuscarinic acetylcholine receptor M4
antagonist
Human
AMuscarinic acetylcholine receptor M5Not AvailableHuman
AVoltage-dependent L-type calcium channel subunit alpha-1C
antagonist
Human
AAlpha-1A adrenergic receptor
antagonist
Human
Absorption

Propiverine is rapidly absorbed from the gastrointestinal tract with maximum plasma concentrations attained after 2.3 hours. the mean absolute bioavailability of mictonorm 15 mg tablets (propiverine) is 40.5 %. It undergoes heavy first-pass metabolism in the liver [6].

Volume of distribution

In one study, the volume of distribution was calculated in 21 healthy volunteers after intravenous (IV) administration of propiverine hydrochloride was measured to range from 125 to 4731 (average 2791) indicating, that a large amount of available propiverine is distributed to peripheral compartments [13].

Protein binding

90-95% for the parent compound and about 60% for the main metabolite [13].

Metabolism

The major metabolites were found to be as follows; 4-piperidyl diphenylpropoxyacetate (DM-P-4), 1-methyl-4-piperidyl benzilate (Dpr-P-4) and 1-methyl-4-piperidyl diphenyl-(2 carboxy) ethoxyacetate (ω-COOH-P-4) in the liver, Dpt-p-4, DM-P-4 in the kidney, and DM-P-4, DPr-P-4 in the lung [12]. In the same pharmacokinetic study, All pharmacologically active compounds such as the unchanged compound, 1-methyl-4-piperidyl benzilate N-oxide (DPr-P-4 (N→O)), Dpt-p-4 and 1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide (P-4 (N→O)) were present in the urinary bladder, a target organ for P-4, at higher concentrations than in the plasma [12].

Propiverine is metabolized by both intestinal and hepatic enzymes. The main metabolic pathway involves the oxidation of the piperidyl-N _and is mediated by _CYP 3A4 and _flavin-containing monooxygenases (FMO) _1 and 3 and results in the formation of the second main metabolite M-5, the plasma concentration of which is greater in concentration that of the parent substance propiverine. Four metabolites have been identified in the urine following propiverine ingestion; 3 them are pharmacologically active metabolites that may contribute to its therapeutic effect (M-5, M-6, M-23) [14].

The mean absolute bioavailability of propiverine IR 15 mg is 40.5% [6].

Route of elimination

Following the ingestion of 30 mg propiverine, 60% radioactivity was recovered in urine and 21% was recovered in feces within 12 days. Less than 1% of an oral dose is excreted unchanged in the urine [6].

Half life

In three studies including a total of 37 healthy volunteers mean elimination half-life was 14.1, 20.1 and 22.1 hours, respectively [6].

Clearance

Mean total clearance after single dose administration of 30 mg is 371 mL/min (191 – 870 mL/min) [6].

Toxicity

The most common adverse reactions reported in patients treated with propiverine include dry mouth, headache, accommodation disorder, constipation, abdominal pain, dyspepsia and fatigue [6].

Propiverine may cause drowsiness and blurred vision. This may impair the ability to exert activities that require mental alertness such as operating a motor vehicle or other machinery, or to perform hazardous work while taking this drug [6].

There have been reports of QT interval prolongation with antimuscarinic medications in the same class of drugs of propiverine hydrochloride. Some drugs that may cause QT/QTc interval prolongation may increase the risk of a rare, but serious ventricular arrhythmia called torsades de pointes. Patients at risk for QT/QTc interval prolongation, such as those with diagnosed heart failure, long QT syndrome, recent significant hypokalemia episodes or receiving other drugs known to prolong QT/QTc, should be closely monitored while treated with propiverine. Patients who experience prolonged QT/QTc or symptoms of possible arrhythmias including dizziness, palpitations or fainting should be electrocardiographically evaluated and monitored for electrolyte disturbances [6].

Propiverine, like other anticholinergics, induces mydriasis. Therefore, the risk to induce acute angle-closure glaucoma in individuals predisposed with narrow angles of the anterior chamber may be increased. Drugs of this class, including propiverine, have been reported to induce or precipitate acute angle-closure glaucoma [6].

No clinical data are available on the use of propiverine in pregnant women. Studies in animals have shown reproductive toxicity [6].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Propiverine can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Propiverine.
1,10-PhenanthrolineThe therapeutic efficacy of Propiverine can be decreased when used in combination with 1,10-Phenanthroline.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Propiverine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Propiverine.
4-MethoxyamphetamineThe therapeutic efficacy of 4-Methoxyamphetamine can be decreased when used in combination with Propiverine.
5-androstenedioneThe metabolism of Propiverine can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Propiverine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Propiverine can be decreased when combined with 6-O-benzylguanine.
AbacavirAbacavir may decrease the excretion rate of Propiverine which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. McKeage K: Propiverine: a review of its use in the treatment of adults and children with overactive bladder associated with idiopathic or neurogenic detrusor overactivity, and in men with lower urinary tract symptoms. Clin Drug Investig. 2013 Jan;33(1):71-91. doi: 10.1007/s40261-012-0046-9. [PubMed:23288694]
  2. Haustein KO, Huller G: On the pharmacokinetics and metabolism of propiverine in man. Eur J Drug Metab Pharmacokinet. 1988 Apr-Jun;13(2):81-90. [PubMed:3208795]
  3. Chess-Williams R: Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol. 2002 Jun;22(3):133-45. [PubMed:12452898]
  4. Maruyama S, Oki T, Otsuka A, Shinbo H, Ozono S, Kageyama S, Mikami Y, Araki I, Takeda M, Masuyama K, Yamada S: Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder. J Urol. 2006 Jan;175(1):365-9. [PubMed:16406943]
  5. Sakakibara F, Takahama K, Nanri M, Sasaki E: Pharmacological Properties of Propiverine Contribute to Improving Lower Urinary Tract Dysfunctions in Rats with Spinal Cord Injuries. Drug Res (Stuttg). 2016 Sep;66(9):464-469. doi: 10.1055/s-0042-110855. Epub 2016 Oct 17. [PubMed:27750360]
  6. Mictoryl monograph [Link]
  7. CDR CLINICAL REVIEW REPORT FOR MICTORYL [Link]
  8. The Efficacy and Safety of Propiverine Hydrochloride in Patients with Overactive Bladder Symptoms Who Poorly Responded to Previous Anticholinergic Agents [Link]
  9. Propiverine hydrochloride [Link]
  10. Propiverine Hydrochloride PubChem [Link]
  11. Public assessment report [Link]
  12. Pharmacokinetic Studies on Propiverine Hydrochloride [Link]
  13. Mictonorm [Link]
  14. The muscarinic receptor antagonist propiverine exhibits α1-adrenoceptor antagonism in human prostate and porcine trigonum [Link]
  15. Mayo Clinic, Overactive Bladder [Link]
  16. Maximizing the Treatment of Overactive Bladder in the Elderly [Link]
  17. Muscarinic receptor antagonists for overactive bladder [Link]
  18. Propiverine overview [Link]
  19. The N-Oxide Metabolite Contributes to Bladder Selectivity Resulting from Oral Propiverine: Muscarinic Receptor Binding and Pharmacokinetics [Link]
External Links
Human Metabolome Database
HMDB0041999
KEGG Drug
D08441
KEGG Compound
C07852
PubChem Compound
4942
PubChem Substance
347828547
ChemSpider
4773
ChEBI
8493
ChEMBL
CHEMBL1078261
Wikipedia
Propiverine
ATC Codes
G04BD06 — Propiverine
AHFS Codes
  • 86:12.04 — Antimuscarinics
MSDS
Download (168 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedNot AvailableUrinary Bladder, Overactive1
3CompletedTreatmentBladder Disorder, Neurogenic / Neurogenic Bladder Disorder / Neurogenic Urinary Bladder Disorder / Overactive Detrusor Function / Urinary Bladder Disorder, Neurogenic / Urinary Bladder Neurogenic Dysfunction / Urinary Bladder, Neurogenic / Urinary Incontinence (UI) / Urologic Diseases1
3CompletedTreatmentUrinary Bladder, Overactive2
4CompletedNot AvailableUrinary Bladder, Overactive1
4CompletedTreatmentUrinary Bladder, Overactive2
Not AvailableActive Not RecruitingNot AvailableUrinary Bladder, Overactive1
Not AvailableCompletedTreatmentUrinary Incontinence (UI)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Capsule, extended releaseOral30 mg
Capsule, extended releaseOral45 mg
TabletOral5 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)224-226http://www.chemicalbook.com/ChemicalProductProperty_EN_CB3855472.htm
boiling point (°C)484.2 MSDS
water solubility5mg/mLhttp://www.chemicalbook.com/ChemicalProductProperty_EN_CB3855472.htm
Predicted Properties
PropertyValueSource
Water Solubility0.00635 mg/mLALOGPS
logP4.16ALOGPS
logP4.25ChemAxon
logS-4.8ALOGPS
pKa (Strongest Basic)8.72ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area38.77 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity107.73 m3·mol-1ChemAxon
Polarizability41.88 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Benzylethers / Piperidines / Trialkylamines / Carboxylic acid esters / Amino acids and derivatives / Monocarboxylic acids and derivatives / Dialkyl ethers / Azacyclic compounds / Organopnictogen compounds / Organic oxides
show 2 more
Substituents
Diphenylmethane / Benzylether / Piperidine / Amino acid or derivatives / Carboxylic acid ester / Tertiary amine / Tertiary aliphatic amine / Carboxylic acid derivative / Dialkyl ether / Ether
show 13 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
diarylmethane (CHEBI:8493)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM1
Uniprot ID
P11229
Uniprot Name
Muscarinic acetylcholine receptor M1
Molecular Weight
51420.375 Da
References
  1. Maruyama S, Oki T, Otsuka A, Shinbo H, Ozono S, Kageyama S, Mikami Y, Araki I, Takeda M, Masuyama K, Yamada S: Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder. J Urol. 2006 Jan;175(1):365-9. [PubMed:16406943]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
G-protein coupled acetylcholine receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM2
Uniprot ID
P08172
Uniprot Name
Muscarinic acetylcholine receptor M2
Molecular Weight
51714.605 Da
References
  1. Maruyama S, Oki T, Otsuka A, Shinbo H, Ozono S, Kageyama S, Mikami Y, Araki I, Takeda M, Masuyama K, Yamada S: Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder. J Urol. 2006 Jan;175(1):365-9. [PubMed:16406943]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM3
Uniprot ID
P20309
Uniprot Name
Muscarinic acetylcholine receptor M3
Molecular Weight
66127.445 Da
References
  1. Maruyama S, Oki T, Otsuka A, Shinbo H, Ozono S, Kageyama S, Mikami Y, Araki I, Takeda M, Masuyama K, Yamada S: Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder. J Urol. 2006 Jan;175(1):365-9. [PubMed:16406943]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Guanyl-nucleotide exchange factor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM4
Uniprot ID
P08173
Uniprot Name
Muscarinic acetylcholine receptor M4
Molecular Weight
53048.65 Da
References
  1. Maruyama S, Oki T, Otsuka A, Shinbo H, Ozono S, Kageyama S, Mikami Y, Araki I, Takeda M, Masuyama K, Yamada S: Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder. J Urol. 2006 Jan;175(1):365-9. [PubMed:16406943]
Kind
Protein
Organism
Human
Pharmacological action
Yes
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM5
Uniprot ID
P08912
Uniprot Name
Muscarinic acetylcholine receptor M5
Molecular Weight
60073.205 Da
References
  1. Maruyama S, Oki T, Otsuka A, Shinbo H, Ozono S, Kageyama S, Mikami Y, Araki I, Takeda M, Masuyama K, Yamada S: Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder. J Urol. 2006 Jan;175(1):365-9. [PubMed:16406943]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1C
Uniprot ID
Q13936
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1C
Molecular Weight
248974.1 Da
References
  1. Maruyama S, Oki T, Otsuka A, Shinbo H, Ozono S, Kageyama S, Mikami Y, Araki I, Takeda M, Masuyama K, Yamada S: Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder. J Urol. 2006 Jan;175(1):365-9. [PubMed:16406943]
  2. The muscarinic receptor antagonist propiverine exhibits α1-adrenoceptor antagonism in human prostate and porcine trigonum [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1A
Uniprot ID
P35348
Uniprot Name
Alpha-1A adrenergic receptor
Molecular Weight
51486.005 Da
References
  1. The muscarinic receptor antagonist propiverine exhibits α1-adrenoceptor antagonism in human prostate and porcine trigonum [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Mictoryl monograph [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Nadp binding
Specific Function
This protein is involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. Form I catalyzes the N-oxygenation of secondary and tertiary amines.
Gene Name
FMO1
Uniprot ID
Q01740
Uniprot Name
Dimethylaniline monooxygenase [N-oxide-forming] 1
Molecular Weight
60310.285 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Trimethylamine monooxygenase activity
Specific Function
Involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. It N-oxygenates primary aliphatic alkylamines as well as secondary and tertiary amines. Plays an impor...
Gene Name
FMO3
Uniprot ID
P31513
Uniprot Name
Dimethylaniline monooxygenase [N-oxide-forming] 3
Molecular Weight
60032.975 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Not Available
Gene Name
CYP2B
Uniprot ID
Q14097
Uniprot Name
CYP2B protein
Molecular Weight
43147.81 Da

Drug created on October 20, 2016 15:48 / Updated on November 18, 2018 13:32