Identification

Name
Tolvaptan
Accession Number
DB06212
Description

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
Thumb
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.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

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.

TargetActionsOrganism
AVasopressin V2 receptor
antagonist
Humans
NVasopressin V1a receptor
antagonist
Humans
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
Learn about our commercial Adverse Effects data.
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Toxicity

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.

Affected organisms
  • Humans and other mammals
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.
DrugInteraction
AbacavirTolvaptan may increase the excretion rate of Abacavir which could result in a lower serum level and potentially a reduction in efficacy.
AbametapirThe serum concentration of Tolvaptan can be increased when it is combined with Abametapir.
AcarboseTolvaptan may increase the excretion rate of Acarbose which could result in a lower serum level and potentially a reduction in efficacy.
AcebutololThe risk or severity of hyperkalemia can be increased when Acebutolol is combined with Tolvaptan.
AceclofenacTolvaptan may increase the excretion rate of Aceclofenac which could result in a lower serum level and potentially a reduction in efficacy.
AcemetacinThe therapeutic efficacy of Tolvaptan can be decreased when used in combination with Acemetacin.
AcetaminophenTolvaptan may increase the excretion rate of Acetaminophen which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Tolvaptan which could result in a higher serum level.
AclidiniumTolvaptan may increase the excretion rate of Aclidinium which could result in a lower serum level and potentially a reduction in efficacy.
AcrivastineTolvaptan may increase the excretion rate of Acrivastine which could result in a lower serum level and potentially a reduction in efficacy.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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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

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
JynarqueTablet30 mg/1OralOtsuka America Pharmaceutical, Inc.2018-04-23Not applicableUS flag
JynarqueTablet15 mg/1OralOtsuka America Pharmaceutical, Inc.2018-04-23Not applicableUS flag
SamscaTablet15 mgOralOtsuka Pharmaceutical Europe Ltd.2009-08-03Not applicableEU flag
SamscaTablet15 mgOralOtsuka Pharmaceutical Co., Ltd.2011-09-22Not applicableCanada flag
SamscaTablet15 mg/1OralOtsuka America Pharmaceutical, Inc.2009-05-19Not applicableUS flag
SamscaTablet30 mgOralOtsuka Pharmaceutical Europe Ltd.2009-08-03Not applicableEU flag
SamscaTablet60 mgOralOtsuka Pharmaceutical Co., Ltd.Not applicableNot applicableCanada flag
SamscaTablet15 mgOralOtsuka Pharmaceutical Europe Ltd.2009-08-03Not applicableEU flag
SamscaTablet30 mgOralOtsuka Pharmaceutical Co., Ltd.2011-09-22Not applicableCanada flag
SamscaTablet30 mg/1OralOtsuka America Pharmaceutical, Inc.2009-05-19Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TolvaptanTablet30 mg/1OralAscend Laboratories, LLC2020-05-21Not applicableUS flag
TolvaptanTablet60 mg/1OralAscend Laboratories, LLC2020-05-21Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
JinarcTolvaptan (15 mg) + Tolvaptan (15 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2020-03-26Not applicableCanada flag
JinarcTolvaptan (60 mg) + Tolvaptan (30 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada flag
JinarcTolvaptan (45 mg) + Tolvaptan (15 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada flag
JinarcTolvaptan (30 mg) + Tolvaptan (15 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2020-03-26Not applicableCanada flag
JinarcTolvaptan (90 mg) + Tolvaptan (30 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada flag
JinarcTolvaptan (60 mg) + Tolvaptan (30 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada flag
JinarcTolvaptan (15 mg) + Tolvaptan (15 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2020-03-26Not applicableCanada flag
JinarcTolvaptan (90 mg) + Tolvaptan (30 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada flag
JinarcTolvaptan (45 mg) + Tolvaptan (15 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada flag
JinarcTolvaptan (30 mg) + Tolvaptan (15 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2020-03-26Not applicableCanada flag

Categories

ATC Codes
C03XA01 — Tolvaptan
Drug Categories
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

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[[email protected]@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
  1. 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. [PubMed:16181825]
  2. 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. [PubMed:21401442]
  3. 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. [PubMed:22130104]
  4. 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. [PubMed:20637957]
KEGG Drug
D01213
PubChem Compound
443894
PubChem Substance
175427060
ChemSpider
391976
RxNav
358257
ChEMBL
CHEMBL344159
ZINC
ZINC000000538658
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tolvaptan
AHFS Codes
  • 40:28.28 — Vasopressin Antagonists
FDA label
Download (468 KB)
MSDS
Download (103 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1
4CompletedNot AvailableHealthy Volunteers1
4CompletedTreatmentAdvanced Cancers1
4CompletedTreatmentAscites / Liver Cirrhosis1
4CompletedTreatmentCardiovascular Heart Disease / Heart Diseases / Heart Failure1
4CompletedTreatmentDecompensated Heart Failure1
4CompletedTreatmentHeart Failure3
4CompletedTreatmentRight Heart Failure / Tricuspid valve incompetence1
4Enrolling by InvitationTreatmentCongestive Heart Failure (CHF)1
4Not Yet RecruitingTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Tablet15 mg
Tablet30 mg
TabletOral15 mg
TabletOral15 mg/1
TabletOral30 mg/1
TabletOral30 mg
TabletOral60 mg
TabletOral7.5 MG
TabletOral60 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5258510No1993-11-022010-11-02US flag
US5753677No1998-05-192020-05-19US flag
US8501730No2013-08-062026-09-01US flag
US5972882No1999-10-262018-12-14US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00124 mg/mLALOGPS
logP4.14ALOGPS
logP5.35ChemAxon
logS-5.6ALOGPS
pKa (Strongest Acidic)11.76ChemAxon
pKa (Strongest Basic)-2.1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area69.64 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity129.16 m3·mol-1ChemAxon
Polarizability48.16 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.961
Blood Brain Barrier+0.8429
Caco-2 permeable-0.5116
P-glycoprotein substrateSubstrate0.6765
P-glycoprotein inhibitor IInhibitor0.5241
P-glycoprotein inhibitor IINon-inhibitor0.5525
Renal organic cation transporterNon-inhibitor0.767
CYP450 2C9 substrateNon-substrate0.7217
CYP450 2D6 substrateNon-substrate0.7662
CYP450 3A4 substrateSubstrate0.7372
CYP450 1A2 substrateNon-inhibitor0.7512
CYP450 2C9 inhibitorNon-inhibitor0.7214
CYP450 2D6 inhibitorNon-inhibitor0.7887
CYP450 2C19 inhibitorNon-inhibitor0.5308
CYP450 3A4 inhibitorInhibitor0.8545
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5874
Ames testNon AMES toxic0.7247
CarcinogenicityNon-carcinogens0.8623
BiodegradationNot ready biodegradable0.9939
Rat acute toxicity2.2269 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9807
hERG inhibition (predictor II)Inhibitor0.682
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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

Targets

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
  1. Aperis G, Alivanis P: Tolvaptan: a new therapeutic agent. Rev Recent Clin Trials. 2011 May;6(2):177-88. [PubMed:20868352]
  2. Dixon MB, Lien YH: Tolvaptan and its potential in the treatment of hyponatremia. Ther Clin Risk Manag. 2008 Dec;4(6):1149-55. [PubMed:19337422]
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
  1. 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. [PubMed:20637957]

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
  1. Aperis G, Alivanis P: Tolvaptan: a new therapeutic agent. Rev Recent Clin Trials. 2011 May;6(2):177-88. [PubMed:20868352]
  2. Dixon MB, Lien YH: Tolvaptan and its potential in the treatment of hyponatremia. Ther Clin Risk Manag. 2008 Dec;4(6):1149-55. [PubMed:19337422]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
  1. 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. [PubMed:20679500]

Drug created on March 19, 2008 10:17 / Updated on September 22, 2020 02:11

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