Identification

Name
Pinaverium
Accession Number
DB09090
Type
Small Molecule
Groups
Approved
Description

Pinaverium is a spasmolytic agent used for functional gastrointestinal disorders. It is a quaternary ammonium compound that acts as an atypical calcium antagonist to restore normal bowel function. It is shown to relieve GI spasm and pain, transit disturbances and other symptoms related to motility disorders [1] and may be considered as effective first-lline therapy for patients with irritable bowel syndrome (IBS) [5]. Pinaverium bromide is the common ingredient in formulations, mostly as oral tablets. Although it is not a currently approved drug by the FDA, pinaverium is available in over 60 countries including Canada.

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Pinaverium bromide7SCF54H12J53251-94-8IKGXLCMLVINENI-UHFFFAOYSA-M
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DicetelTablet50 mgOralBgp Pharma Ulc1993-12-31Not applicableCanada
DicetelTablet100 mgOralBgp Pharma Ulc1999-07-05Not applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-pinaveriumTablet50 mgOralApotex CorporationNot applicableNot applicableCanada
International/Other Brands
Alevian Duo (Takeda) / Blocafer (Liferpal, Mexico) / Delibs (CONMED, Taiwan) / Ilyang Dicetel (Ilyang) / Nulite (Dominguez, Argentina) / Pakab (Wermar, Mexico) / Pinar (ABL Pharma, Peru) / Pinaven (Johnson, Taiwan) / Pladuet (Interlab Pharmaceutica, Mexico) / Planex (Rimsa, Mexico) / Riginal (Royal Pharma, Chile) / Spascolon (Chemi ph, Egypt) / Spasmopinaver (GNP, Egypt) / Spastec (Swiss Pharm, Taiwan) / Sucam (Everest, Taiwan) / Zerpyco (Atlantis, Mexico)
Categories
UNII
U2368VVE7O
CAS number
59995-65-2
Weight
Average: 511.52
Monoisotopic: 510.221348
Chemical Formula
C26H41BrNO4
InChI Key
DDHUTBKXLWCZCO-UHFFFAOYSA-N
InChI
InChI=1S/C26H41BrNO4/c1-26(2)21-6-5-19(22(26)16-21)7-11-31-12-8-28(9-13-32-14-10-28)18-20-15-24(29-3)25(30-4)17-23(20)27/h15,17,19,21-22H,5-14,16,18H2,1-4H3/q+1
IUPAC Name
4-[(2-bromo-4,5-dimethoxyphenyl)methyl]-4-[2-(2-{6,6-dimethylbicyclo[3.1.1]heptan-2-yl}ethoxy)ethyl]morpholin-4-ium
SMILES
COC1=C(OC)C=C(C[N+]2(CCOCCC3CCC4CC3C4(C)C)CCOCC2)C(Br)=C1

Pharmacology

Indication

Indicated for the treatment and relief of symptoms associated with irritable bowel syndrome (IBS) associated with abdominal pain, bowel disturbances and intestinal discomfort, as well as the treatment of symptoms related to functional disorders of the biliary tract.

Associated Conditions
Pharmacodynamics

Pinaverium is a selective and specific voltage-dependent calcium channel blocker located on intestinal smooth muscle cells to inhibit calcium influx. It mediates various effects on the GI tract: it causes oesophageal, gastric and duodenal relaxation, relaxes the colon and intestines, inhibits colonic motility in response to food, hormonal or pharmacological stimuli, accelerates gastric emptying, and reduces contractions of the gallbladder and phasic contractions of sphincter of Oddi [10, 5]. At higher concentrations, pinaverium also exhibits very weak anticholinergic effects [10] but is not shown to display vasodilatory or anti-arrythmic actions [9].

Mechanism of action

Pinaverium interacts with the 1,4-dihydropyridine binding sites on voltage dependent L-type calcium channels located on GI smooth muscle cells in a competitve manner [2]. The binding site is located in the alpha 1S subunit and pinaverium most likely antagonizes the action of calcium ions by stabilizing a non-conducting channel state [8]. Pinaverium inhibits smooth muscle contractions of the GI tract by inhibiting inward calcium current and calcium influx. It is suggested that pinaverium may be able to bind to both closed or inactivates states of the calcium channel with similar affinity [9, 1].

TargetActionsOrganism
AVoltage-dependent L-type calcium channel subunit alpha-1S
antagonist
inhibitor
Human
Absorption

After oral administration, pinaverium is poorly absorbed (5-10%) followed by uptake by liver. Poor absorption is due to its highly polar quaternary ammonium group and high molecular weight [10], which limits extensive diffusion across all cell membranes and promotes its selectivity towards the gastrointestinal tracts []. Peak plasma concentration is reached within one hour after administration and the absolute oral bioavailability is reported to be less than 1%.

Volume of distribution

It is selectively distributed to the digestive tract due to poor absorption and marked hepatobiliary excretion [10].

Protein binding

Pinaverium is highly bound to human plasma proteins with the ratio of 97% [10].

Metabolism

Hepatic metabolism of pinaverium involves demethylation of one of the methoxy groups, hydroxylation of the norpinanyl ring and elimination of the benzyl group with subsequent opening of the morpholine ring [10].

Route of elimination

Pinaverium is predominantly eliminated into feces [10].

Half life

The mean elimination half life is approximately 1.5 hours [10].

Clearance
Not Available
Toxicity

Some minor GI-related adverse effects include epigastric pain and/or fullness, nausea, constipation, heartburn, distension, and diarrhoea. Other side effects are headache, dry mouth, drowsiness, vertigo and skin allergy. Oral LD50 in mice, rats and rabbits are 1531 mg/kg, 1145 mg/kg and 154 mg/kg, respectively [10]. Pinaverium displays no teratogenic, mutagenic or carcinogenic potential.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Pinaverium can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Pinaverium.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Pinaverium is combined with 2,4-thiazolidinedione.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Pinaverium.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Pinaverium.
5-androstenedioneThe metabolism of Pinaverium can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Pinaverium can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Pinaverium.
AbafunginThe therapeutic efficacy of Abafungin can be increased when used in combination with Pinaverium.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Pinaverium.
Food Interactions
Not Available

References

General References
  1. Christen MO: Action of pinaverium bromide, a calcium-antagonist, on gastrointestinal motility disorders. Gen Pharmacol. 1990;21(6):821-5. [PubMed:2177709]
  2. Feron O, Wibo M, Christen MO, Godfraind T: Interaction of pinaverium (a quaternary ammonium compound) with 1,4-dihydropyridine binding sites in rat ileum smooth muscle. Br J Pharmacol. 1992 Feb;105(2):480-4. [PubMed:1313732]
  3. Baumgartner A, Drack E, Halter F, Scheurer U: Effects of pinaverium bromide and verapamil on the motility of the rat isolated colon. Br J Pharmacol. 1985 Sep;86(1):89-94. [PubMed:4052731]
  4. Zheng L, Lai Y, Lu W, Li B, Fan H, Yan Z, Gong C, Wan X, Wu J, Huang D, Wang Y, Mei Y, Li Z, Jiang Z, Liu X, Ye J, Yang Y, Huang H, Xiao J: Pinaverium Reduces Symptoms of Irritable Bowel Syndrome in a Multicenter, Randomized, Controlled Trial. Clin Gastroenterol Hepatol. 2015 Jul;13(7):1285-1292.e1. doi: 10.1016/j.cgh.2015.01.015. Epub 2015 Jan 26. [PubMed:25632806]
  5. Bobo MH, Magous R, Christen MO, Bali JP: Effect of pinaverium and other calcium channel blockers on contraction of isolated gastric antral smooth muscle cells caused by gastrointestinal hormones. Life Sci. 1994;54(25):1947-54. [PubMed:8201843]
  6. Awad R, Dibildox M, Ortiz F: Irritable bowel syndrome treatment using pinaverium bromide as a calcium channel blocker. A randomized double-blind placebo-controlled trial. Acta Gastroenterol Latinoam. 1995;25(3):137-44. [PubMed:8600700]
  7. Itoh Z, Takahashi I: Inhibitory effect of pinaverium bromide on gastrointestinal contractile activity in conscious dogs. Arzneimittelforschung. 1981;31(9):1450-3. [PubMed:7197953]
  8. Tikhonov DB, Zhorov BS: Structural model for dihydropyridine binding to L-type calcium channels. J Biol Chem. 2009 Jul 10;284(28):19006-17. doi: 10.1074/jbc.M109.011296. Epub 2009 May 5. [PubMed:19416978]
  9. Godfraind T, Govoni S, Paoletti R, Vanhoutte PM (2013). Calcium Antagonists: Pharmacology and Clinical Research (pp. 306-307). Springer Science & Business Media. [ISBN:940111725X]
  10. BGP Pharma ULC: DICETEL (Pinaverium Bromide) product monograph [Link]
External Links
PubChem Compound
40704
PubChem Substance
310265017
ChemSpider
37182
ChEBI
135811
ChEMBL
CHEMBL1909324
Wikipedia
Pinaverium
ATC Codes
A03AX04 — Pinaverium
AHFS Codes
  • 56:92.00 — Miscellaneous GI Drugs

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedDiagnosticMalignancies1
4RecruitingTreatmentSphincter of Oddi Dysfunction1
Not AvailableActive Not RecruitingTreatmentIrritable Bowel Syndrome (IBS)1
Not AvailableUnknown StatusTreatmentIrritable Bowel Syndrome (IBS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral100 mg
TabletOral50 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)152-158Product monograph
water solubilitySlightly solubleProduct monograph
Predicted Properties
PropertyValueSource
Water Solubility3.42e-06 mg/mLALOGPS
logP3.71ALOGPS
logP0.67ChemAxon
logS-8.2ALOGPS
pKa (Strongest Acidic)17.16ChemAxon
pKa (Strongest Basic)-3.8ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area36.92 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity143.32 m3·mol-1ChemAxon
Polarizability54.41 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as bicyclic monoterpenoids. These are monoterpenoids containing exactly 2 rings, which are fused to each other.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Prenol lipids
Sub Class
Monoterpenoids
Direct Parent
Bicyclic monoterpenoids
Alternative Parents
Aromatic monoterpenoids / Dimethoxybenzenes / Phenylmethylamines / Phenoxy compounds / Anisoles / Benzylamines / Alkyl aryl ethers / Aralkylamines / Bromobenzenes / Morpholines
show 10 more
Substituents
Aromatic monoterpenoid / Bicyclic monoterpenoid / Pinane monoterpenoid / Dimethoxybenzene / O-dimethoxybenzene / Phenoxy compound / Benzylamine / Anisole / Methoxybenzene / Phenol ether
show 30 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
Inhibitor
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
CACNA1S
Uniprot ID
Q13698
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1S
Molecular Weight
212348.1 Da
References
  1. Tikhonov DB, Zhorov BS: Structural model for dihydropyridine binding to L-type calcium channels. J Biol Chem. 2009 Jul 10;284(28):19006-17. doi: 10.1074/jbc.M109.011296. Epub 2009 May 5. [PubMed:19416978]
  2. Feron O, Wibo M, Christen MO, Godfraind T: Interaction of pinaverium (a quaternary ammonium compound) with 1,4-dihydropyridine binding sites in rat ileum smooth muscle. Br J Pharmacol. 1992 Feb;105(2):480-4. [PubMed:1313732]

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. Uesawa Y, Takeuchi T, Mohri K: Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17. [PubMed:22039822]

Drug created on September 15, 2015 15:22 / Updated on November 14, 2018 12:57