Identification
- Summary
Tolvaptan is a selective vasopressin V2-receptor antagonist to slow kidney function decline in patients at risk for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Also used to treat hypervolemic and euvolemic hyponatremia.
- Brand Names
- Jinarc, Jynarque 45/15 Carton, Samsca
- Generic Name
- Tolvaptan
- DrugBank Accession Number
- DB06212
- Background
Tolvaptan is used to treat low blood sodium levels (hyponatremia) associated with various conditions like congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormones (SIADH). FDA approved on May 19, 2009.
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Tolvaptan (DB06212)
- Weight
- Average: 448.941
Monoisotopic: 448.155370383 - Chemical Formula
- C26H25ClN2O3
- Synonyms
- Not Available
- External IDs
- OPC-41061
Pharmacology
- Indication
Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and cirrhosis.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Autosomal dominant polycystic kidney disease •••••••••••• •••••• Treatment of Symptomatic euvolemic hyponatremia •••••••••••• Treatment of Symptomatic hypervolemic hyponatremia •••••••••••• - Contraindications & Blackbox Warnings
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Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan. Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours. The magnitude of serum sodium and osmolality change increases with escalating doses. Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan. The affinity for V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 receptors.
- Mechanism of action
Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls thus preventing water absorption. This action ultimately results in an increase in urine volume, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin.
Target Actions Organism AVasopressin V2 receptor antagonistHumans NVasopressin V1a receptor antagonistHumans - Absorption
Tmax, Healthy subjects: 2 - 4 hours; Cmax, Healthy subjects, 30 mg: 374 ng/mL; Cmax, Healthy subjects, 90 mg: 418 ng/mL; Cmax, heart failure patients, 30 mg: 460 ng/mL; Cmax, heart failure patients, 90 mg: 723 ng/mL; AUC(0-24 hours), 60 mg: 3.71 μg·h/mL; AUC(∞), 60 mg: 4.55 μg·h/mL; The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Food does not impact the bioavailability of tolvaptan.
- Volume of distribution
Healthy subjects: 3L/kg; slightly higher in heart failure patients.
- Protein binding
99% bound
- Metabolism
Metabolism exclusively by CYP3A4 enzyme in the liver. Metabolites are inactive.
- Route of elimination
Fecal- very little renal elimination (<1% is excreted unchanged in the urine)
- Half-life
Terminal half life, oral dose = 12 hours.
- Clearance
4 mL/min/kg (post-oral dosing).
- Adverse Effects
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The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Tolvaptan may increase the excretion rate of Abacavir which could result in a lower serum level and potentially a reduction in efficacy. Abametapir The serum concentration of Tolvaptan can be increased when it is combined with Abametapir. Abatacept The metabolism of Tolvaptan can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Tolvaptan. Abrocitinib The serum concentration of Tolvaptan can be increased when it is combined with Abrocitinib. - Food Interactions
- Avoid excessive or chronic alcohol consumption. This may increase the risk of developing osmotic demyelination syndrome.
- Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of tolvaptan, which may increase its serum concentration.
- Avoid St. John's Wort. This herb induces the CYP3A metabolism of tolvaptan and may reduce its serum concentration.
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Jinarc Tablet 30 mg Oral Otsuka Pharmaceutical Netherlands B.V. 2020-12-16 Not applicable EU 
Jinarc Tablet 15 mg Oral Otsuka Pharmaceutical Netherlands B.V. 2020-12-16 Not applicable EU Jinarc Tablet 30 mg Oral Otsuka Pharmaceutical Netherlands B.V. 2020-12-16 Not applicable EU Jinarc Tablet 15 mg Oral Otsuka Pharmaceutical Netherlands B.V. 2020-12-16 Not applicable EU Jynarque Tablet 30 mg/1 Oral Otsuka America Pharmaceutical, Inc. 2018-04-23 Not applicable US 
- Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tolvaptan Tablet 15 mg/1 Oral Apotex Corp. 2022-12-14 Not applicable US Tolvaptan Tablet 30 mg/1 Oral Apotex Corp. 2022-07-05 Not applicable US Tolvaptan Tablet 30 mg/1 Oral Camber Pharmaceuticals, Inc. 2021-07-16 Not applicable US Tolvaptan Tablet 30 mg/1 Oral Apotex Corp. 2020-05-20 2023-11-30 US Tolvaptan Tablet 30 mg/1 Oral Novadoz Pharmaceuticals Llc 2023-06-21 Not applicable US - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image JINARC Tolvaptan (15 MG) + Tolvaptan (45 MG) Tablet Oral Otsuka Pharmaceutical Netherlands Bv 2020-05-11 Not applicable Italy 
Jinarc Tolvaptan (60 mg) + Tolvaptan (30 mg) Tablet Oral Otsuka Pharmaceutical Co., Ltd. 2015-06-01 Not applicable Canada 
JINARC Tolvaptan (30 MG) + Tolvaptan (60 MG) Tablet Oral Otsuka Pharmaceutical Netherlands Bv 2017-09-27 Not applicable Italy JINARC Tolvaptan (30 MG) + Tolvaptan (90 MG) Tablet Oral Otsuka Pharmaceutical Netherlands Bv 2017-09-27 Not applicable Italy Jinarc Tolvaptan (30 mg) + Tolvaptan (15 mg) Tablet Oral Otsuka Pharmaceutical Co., Ltd. 2020-03-26 Not applicable Canada
Categories
- ATC Codes
- C03XA01 — Tolvaptan
- Drug Categories
- Agents causing hyperkalemia
- Antidiuretic Hormone Receptor Antagonists
- Benzazepines
- Cardiovascular Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Diuretics
- Heterocyclic Compounds, Fused-Ring
- Narrow Therapeutic Index Drugs
- Natriuretic Agents
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Vasopressin V2 Receptor Antagonist
- Vasopressin V2 Receptor Antagonists
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as benzanilides. These are aromatic compounds containing an anilide group in which the carboxamide group is substituted with a benzene ring. They have the general structure RNC(=O)R', where R,R'= benzene.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Anilides
- Direct Parent
- Benzanilides
- Alternative Parents
- Benzazepines / o-Toluamides / Benzamides / Benzoyl derivatives / Azepines / Aryl chlorides / Tertiary carboxylic acid amides / Secondary carboxylic acid amides / Secondary alcohols / Azacyclic compounds show 5 more
- Substituents
- Alcohol / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azepine / Benzamide / Benzanilide / Benzazepine / Benzoic acid or derivatives show 19 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 1E2497LPNY
- CAS number
- 150683-30-0
- InChI Key
- GYHCTFXIZSNGJT-XMMPIXPASA-N
- InChI
- InChI=1S/C26H25ClN2O3/c1-16-6-3-4-7-20(16)25(31)28-19-10-11-21(17(2)14-19)26(32)29-13-5-8-24(30)22-15-18(27)9-12-23(22)29/h3-4,6-7,9-12,14-15,24,30H,5,8,13H2,1-2H3,(H,28,31)/t24-/m1/s1
- IUPAC Name
- N-{4-[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]-3-methylphenyl}-2-methylbenzamide
- SMILES
- CC1=CC=CC=C1C(=O)NC1=CC(C)=C(C=C1)C(=O)N1CCC[C@@H](O)C2=C1C=CC(Cl)=C2
References
- Synthesis Reference
Bandi Parthasaradhi Reddy, "PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES." U.S. Patent US20130190490, issued July 25, 2013.
US20130190490- General References
- Gheorghiade M, Teerlink JR, Mebazaa A: Pharmacology of new agents for acute heart failure syndromes. Am J Cardiol. 2005 Sep 19;96(6A):68G-73G. [Article]
- Ambrosy A, Goldsmith SR, Gheorghiade M: Tolvaptan for the treatment of heart failure: a review of the literature. Expert Opin Pharmacother. 2011 Apr;12(6):961-76. doi: 10.1517/14656566.2011.567267. Epub 2011 Mar 15. [Article]
- Yi S, Jeon H, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS: Pharmacokinetics and pharmacodynamics of oral tolvaptan administered in 15- to 60-mg single doses to healthy Korean men. J Cardiovasc Pharmacol. 2012 Apr;59(4):315-22. doi: 10.1097/FJC.0b013e318241e89c. [Article]
- Nemerovski C, Hutchinson DJ: Treatment of hypervolemic or euvolemic hyponatremia associated with heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone with tolvaptan: a clinical review. Clin Ther. 2010 Jun;32(6):1015-32. doi: 10.1016/j.clinthera.2010.06.015. [Article]
- External Links
- KEGG Drug
- D01213
- PubChem Compound
- 443894
- PubChem Substance
- 175427060
- ChemSpider
- 391976
- 358257
- ChEMBL
- CHEMBL344159
- ZINC
- ZINC000000538658
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Tolvaptan
- FDA label
- Download (468 KB)
- MSDS
- Download (103 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Not Available Healthy Volunteers (HV) 1 4 Completed Treatment Acute Decompensated Heart Failure (ADHF) 1 4 Completed Treatment Advanced Malignant Neoplasm 1 4 Completed Treatment Ascites / Cirrhosis of the Liver 1 4 Completed Treatment Autosomal Dominant Polycystic Kidney Disease （ADPKD) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Kit; tablet Oral Tablet Oral Tablet Oral 15 mg/1 Tablet Oral 30 mg Tablet Oral 30 mg/1 Tablet Oral 60 mg Tablet Oral 7.5 MG Tablet Oral 15 mg Tablet Oral 60 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US5258510 No 1993-11-02 2010-11-02 US US5753677 No 1998-05-19 2020-05-19 US US8501730 No 2013-08-06 2026-09-01 US US5972882 No 1999-10-26 2018-12-14 US US10905694 No 2021-02-02 2030-04-07 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00124 mg/mL ALOGPS logP 4.14 ALOGPS logP 5.35 Chemaxon logS -5.6 ALOGPS pKa (Strongest Acidic) 14.19 Chemaxon pKa (Strongest Basic) -2.1 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 69.64 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 129.16 m3·mol-1 Chemaxon Polarizability 48.16 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.961 Blood Brain Barrier + 0.8429 Caco-2 permeable - 0.5116 P-glycoprotein substrate Substrate 0.6765 P-glycoprotein inhibitor I Inhibitor 0.5241 P-glycoprotein inhibitor II Non-inhibitor 0.5525 Renal organic cation transporter Non-inhibitor 0.767 CYP450 2C9 substrate Non-substrate 0.7217 CYP450 2D6 substrate Non-substrate 0.7662 CYP450 3A4 substrate Substrate 0.7372 CYP450 1A2 substrate Non-inhibitor 0.7512 CYP450 2C9 inhibitor Non-inhibitor 0.7214 CYP450 2D6 inhibitor Non-inhibitor 0.7887 CYP450 2C19 inhibitor Non-inhibitor 0.5308 CYP450 3A4 inhibitor Inhibitor 0.8545 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5874 Ames test Non AMES toxic 0.7247 Carcinogenicity Non-carcinogens 0.8623 Biodegradation Not ready biodegradable 0.9939 Rat acute toxicity 2.2269 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9807 hERG inhibition (predictor II) Inhibitor 0.682
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0fr2-0560900000-b34797d4cc8f9363101a Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-01r2-2006900000-5eca15604040a7acf4fe Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00lr-0511900000-c8219d11b42dac8f5320 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-001j-7003900000-8ecb6457df4e63c41729 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00mp-9000100000-823fbaa752740d49a6cf Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9502200000-82913a0695b2276d46c3 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 207.46486 predictedDeepCCS 1.0 (2019) [M+H]+ 209.86043 predictedDeepCCS 1.0 (2019) [M+Na]+ 216.10521 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Vasopressin receptor activity
- Specific Function
- Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption.
- Gene Name
- AVPR2
- Uniprot ID
- P30518
- Uniprot Name
- Vasopressin V2 receptor
- Molecular Weight
- 40278.57 Da
References
- Aperis G, Alivanis P: Tolvaptan: a new therapeutic agent. Rev Recent Clin Trials. 2011 May;6(2):177-88. [Article]
- Dixon MB, Lien YH: Tolvaptan and its potential in the treatment of hyponatremia. Ther Clin Risk Manag. 2008 Dec;4(6):1149-55. [Article]
- Mondritzki T, Mai TA, Vogel J, Pook E, Wasnaire P, Schmeck C, Huser J, Dinh W, Truebel H, Kolkhof P: Cardiac output improvement by pecavaptan: a novel dual-acting vasopressin V1a/V2 receptor antagonist in experimental heart failure. Eur J Heart Fail. 2021 May;23(5):743-750. doi: 10.1002/ejhf.2001. Epub 2020 Oct 9. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Antagonist
- General Function
- Vasopressin receptor activity
- Specific Function
- Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system. Has been involved in social behavi...
- Gene Name
- AVPR1A
- Uniprot ID
- P37288
- Uniprot Name
- Vasopressin V1a receptor
- Molecular Weight
- 46799.105 Da
References
- Nemerovski C, Hutchinson DJ: Treatment of hypervolemic or euvolemic hyponatremia associated with heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone with tolvaptan: a clinical review. Clin Ther. 2010 Jun;32(6):1015-32. doi: 10.1016/j.clinthera.2010.06.015. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- Shoaf SE, Ohzone Y, Ninomiya S, Furukawa M, Bricmont P, Kashiyama E, Mallikaarjun S: In vitro P-glycoprotein interactions and steady-state pharmacokinetic interactions between tolvaptan and digoxin in healthy subjects. J Clin Pharmacol. 2011 May;51(5):761-9. doi: 10.1177/0091270010376193. Epub 2010 Aug 2. [Article]
Drug created at March 19, 2008 16:17 / Updated at August 31, 2022 19:25