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
Structure for Pinaverium (DB09090)
- Synonyms
- Not Available
- Product Ingredients
Ingredient UNII CAS InChI Key Pinaverium bromide 7SCF54H12J 53251-94-8 IKGXLCMLVINENI-UHFFFAOYSA-M - Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Dicetel Tablet 50 mg Oral Bgp Pharma Ulc 1993-12-31 Not applicable Canada 
Dicetel Tablet 100 mg Oral Bgp Pharma Ulc 1999-07-05 Not applicable Canada - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Apo-pinaverium Tablet 50 mg Oral Apotex Corporation Not applicable Not applicable Canada - 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
- Agents causing hyperkalemia
- Alimentary Tract and Metabolism
- Antiarrhythmic agents
- Autonomic Agents
- Bradycardia-Causing Agents
- Calcium Channel Blockers
- Cardiovascular Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Drugs for Functional Gastrointestinal Disorders
- Membrane Transport Modulators
- Miscellaneous GI Drugs
- Oxazines
- Parasympatholytics
- Peripheral Nervous System Agents
- Potential QTc-Prolonging Agents
- QTc Prolonging Agents
- Vasodilating Agents
- 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].
Target Actions Organism AVoltage-dependent L-type calcium channel subunit alpha-1S antagonistinhibitorHumans - 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
Drug Interaction (R)-warfarin The metabolism of Pinaverium can be decreased when combined with (R)-warfarin. (S)-Warfarin The metabolism of (S)-Warfarin can be decreased when combined with Pinaverium. 2,4-thiazolidinedione The risk or severity of hypoglycemia can be increased when Pinaverium is combined with 2,4-thiazolidinedione. 3,5-diiodothyropropionic acid The metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Pinaverium. 4-hydroxycoumarin The metabolism of 4-hydroxycoumarin can be decreased when combined with Pinaverium. 5-androstenedione The metabolism of Pinaverium can be decreased when combined with 5-androstenedione. 6-Deoxyerythronolide B The metabolism of Pinaverium can be decreased when combined with 6-Deoxyerythronolide B. 6-O-benzylguanine The metabolism of 6-O-benzylguanine can be decreased when combined with Pinaverium. 7-ethyl-10-hydroxycamptothecin The metabolism of Pinaverium can be decreased when combined with 7-ethyl-10-hydroxycamptothecin. 9-aminocamptothecin The metabolism of 9-aminocamptothecin can be decreased when combined with Pinaverium. - Food Interactions
- Not Available
References
- General References
- Christen MO: Action of pinaverium bromide, a calcium-antagonist, on gastrointestinal motility disorders. Gen Pharmacol. 1990;21(6):821-5. [PubMed:2177709]
- 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]
- 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]
- 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]
- 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]
- 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]
- Itoh Z, Takahashi I: Inhibitory effect of pinaverium bromide on gastrointestinal contractile activity in conscious dogs. Arzneimittelforschung. 1981;31(9):1450-3. [PubMed:7197953]
- 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]
- Godfraind T, Govoni S, Paoletti R, Vanhoutte PM (2013). Calcium Antagonists: Pharmacology and Clinical Research (pp. 306-307). Springer Science & Business Media. [ISBN:940111725X]
- BGP Pharma ULC: DICETEL (Pinaverium Bromide) product monograph [Link]
- External Links
- PubChem Compound
- 40704
- PubChem Substance
- 310265017
- ChemSpider
- 37182
- BindingDB
- 50101975
- ChEBI
- 135811
- ChEMBL
- CHEMBL1909324
- Wikipedia
- Pinaverium
- ATC Codes
- A03AX04 — Pinaverium
- AHFS Codes
- 56:92.00 — Miscellaneous GI Drugs
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Diagnostic Malignancies 1 4 Recruiting Treatment Sphincter of Oddi Dysfunction 1 Not Available Active Not Recruiting Treatment Irritable Bowel Syndrome (IBS) 1 Not Available Unknown Status Treatment Irritable Bowel Syndrome (IBS) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Tablet Oral 100 mg Tablet Oral 50 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 152-158 Product monograph water solubility Slightly soluble Product monograph - Predicted Properties
Property Value Source Water Solubility 3.42e-06 mg/mL ALOGPS logP 3.71 ALOGPS logP 0.67 ChemAxon logS -8.2 ALOGPS pKa (Strongest Acidic) 17.16 ChemAxon pKa (Strongest Basic) -3.8 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 4 ChemAxon Hydrogen Donor Count 0 ChemAxon Polar Surface Area 36.92 Å2 ChemAxon Rotatable Bond Count 10 ChemAxon Refractivity 143.32 m3·mol-1 ChemAxon Polarizability 54.41 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 1 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule Yes ChemAxon MDDR-like Rule Yes ChemAxon - 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
- Humans
- Pharmacological action
- Yes
- Actions
- AntagonistInhibitor
- 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
- 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]
- 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
- Humans
- 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
- 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 February 19, 2019 09:00