Identification

Name
Tolvaptan
Accession Number
DB06212
Type
Small Molecule
Groups
Approved
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.

Structure
Thumb
Synonyms
Not Available
External IDs
OPC-41061
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
JynarqueTablet30 mg/1OralOtsuka America Pharmaceutical, Inc.2018-04-23Not applicableUs
JynarqueTablet15 mg/1OralOtsuka America Pharmaceutical, Inc.2018-04-23Not applicableUs
SamscaTablet15 mgOralOtsuka Pharmaceutical Europe Ltd.2009-08-03Not applicableEu
SamscaTablet60 mgOralOtsuka Pharmaceutical Co., Ltd.Not applicableNot applicableCanada
SamscaTablet30 mgOralOtsuka Pharmaceutical Europe Ltd.2009-08-03Not applicableEu
SamscaTablet30 mg/1OralOtsuka Pharmaceutical Co., Ltd.2009-05-19Not applicableUs
SamscaTablet15 mgOralOtsuka Pharmaceutical Co., Ltd.2011-09-22Not applicableCanada
SamscaTablet15 mgOralOtsuka Pharmaceutical Europe Ltd.2009-08-03Not applicableEu
SamscaTablet15 mg/1OralOtsuka Pharmaceutical Co., Ltd.2009-05-19Not applicableUs
SamscaTablet30 mgOralOtsuka Pharmaceutical Europe Ltd.2009-08-03Not applicableEu
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
JinarcTolvaptan (15 mg) + Tolvaptan (45 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada
JinarcTolvaptan (30 mg) + Tolvaptan (60 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada
JinarcTolvaptan (30 mg) + Tolvaptan (90 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada
JinarcTolvaptan (15 mg) + Tolvaptan (45 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada
JinarcTolvaptan (30 mg) + Tolvaptan (60 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada
JinarcTolvaptan (30 mg) + Tolvaptan (90 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.2015-06-01Not applicableCanada
JynarqueTolvaptan (15 mg/1) + Tolvaptan (45 mg/1)KitOtsuka America Pharmaceutical, Inc.2018-04-23Not applicableUs
JynarqueTolvaptan (30 mg/1) + Tolvaptan (60 mg/1)KitOtsuka America Pharmaceutical, Inc.2018-04-23Not applicableUs
JynarqueTolvaptan (30 mg/1) + Tolvaptan (90 mg/1)KitOtsuka America Pharmaceutical, Inc.2018-04-23Not applicableUs
JynarqueTolvaptan (15 mg/1) + Tolvaptan (45 mg/1)KitOtsuka America Pharmaceutical, Inc.2018-04-23Not applicableUs
International/Other Brands
Samsca
Categories
UNII
1E2497LPNY
CAS number
150683-30-0
Weight
Average: 448.941
Monoisotopic: 448.155370383
Chemical Formula
C26H25ClN2O3
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

Pharmacology

Indication

Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and cirrhosis.

Associated Conditions
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
Human
NVasopressin V1a receptor
antagonist
Human
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).

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
DrugInteraction
(R)-warfarinThe metabolism of Tolvaptan can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Tolvaptan can be decreased when combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidTolvaptan may increase the hyperkalemic activities of 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
3,5-diiodothyropropionic acidThe metabolism of Tolvaptan can be decreased when combined with 3,5-diiodothyropropionic acid.
4-hydroxycoumarinThe metabolism of Tolvaptan can be decreased when combined with 4-hydroxycoumarin.
5-androstenedioneThe metabolism of Tolvaptan can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Tolvaptan can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Tolvaptan can be decreased when combined with 6-O-benzylguanine.
9-aminocamptothecinThe metabolism of Tolvaptan can be decreased when combined with 9-aminocamptothecin.
AbemaciclibThe metabolism of Tolvaptan can be decreased when combined with Abemaciclib.
Food Interactions
Not Available

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]
External Links
KEGG Drug
D01213
PubChem Compound
443894
PubChem Substance
175427060
ChemSpider
391976
ChEMBL
CHEMBL344159
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Tolvaptan
ATC Codes
C03XA01 — Tolvaptan
AHFS Codes
  • 40:28.28 — Vasopressin Antagonists
FDA label
Download (468 KB)
MSDS
Download (103 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceNephrolithiasis, Calcium Oxalate / Nephrolithiasis, Calcium Phosphate1
1CompletedTreatmentAscites / Hepatic Cirrhosis1
1CompletedTreatmentHealthy Adult Males1
1CompletedTreatmentHealthy Volunteers1
1RecruitingTreatmentCongestive Heart Failure (CHF) / Prophylaxis of cardiomyopathy1
1, 2CompletedBasic ScienceSyndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)1
2CompletedTreatmentAscites / Hepatic Cirrhosis1
2CompletedTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)6
2CompletedTreatmentCarcinomatous Edema1
2CompletedTreatmentCardiovascular Disease (CVD) / Renal Dysfunction1
2CompletedTreatmentChronic Renal Failure (CRF)3
2CompletedTreatmentCongestive Heart Failure (CHF)3
2CompletedTreatmentCongestive Heart Failure (CHF) / Edema1
2CompletedTreatmentHypovolemic Hyponatremia1
2CompletedTreatmentLiver Cirrhosis1
2CompletedTreatmentRenal Dysfunction1
2Not Yet RecruitingTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1
2TerminatedTreatmentHyponatremias1
2, 3Active Not RecruitingTreatmentLiver Cirrhosis / Refractory/Recurrent Ascites1
2, 3Unknown StatusTreatmentNon-hypovolemic Non-acute Hyponatremia1
3Active Not RecruitingTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1
3CompletedNot AvailableHyponatremias / Liver Cirrhosis1
3CompletedTreatmentAscites / Hepatic Cirrhosis1
3CompletedTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)4
3CompletedTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD) / Chronic Kidney Disease (CKD)1
3CompletedTreatmentCardiac-induced Edema1
3CompletedTreatmentCongestive Heart Failure (CHF)1
3CompletedTreatmentDyspnea / Heart Failure, Unspecified1
3CompletedTreatmentEdema, Cardiac3
3CompletedTreatmentHeart Failure, Unspecified1
3CompletedTreatmentHepatic Encephalopathy / Hyponatremias / Liver Cirrhosis1
3CompletedTreatmentHyponatremias2
3CompletedTreatmentHyponatremias / Inappropriate ADH Syndrome / Water Intoxication / Water-Electrolyte Imbalance1
3CompletedTreatmentHyponatremias / Inappropriate ADH Syndrome / Water Intoxication / Water-Electrolyte Imbalances1
3CompletedTreatmentLiver Cirrhosis3
3Not Yet RecruitingTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1
3RecruitingTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1
3RecruitingTreatmentPediatric Congestive Heart Failure (CHF) Patients With Volume Overload1
3RecruitingTreatmentSyndrome of Inappropriate Antidiuretic Hormone Secretion1
3TerminatedTreatmentDilutional Hyponatremia / Hyponatremias / Inappropriate ADH Syndrome1
3TerminatedTreatmentHyponatremias2
3Unknown StatusTreatmentAcute Heart Failure (AHF)1
3WithdrawnTreatmentHyponatremias1
4Active Not RecruitingTreatmentHeart Failure, Unspecified1
4CompletedNot AvailableHealthy Volunteers1
4CompletedTreatmentAcute Decompensated Heart Failure (ADHF)1
4CompletedTreatmentAdvanced Cancers1
4CompletedTreatmentAscites / Liver Cirrhosis1
4CompletedTreatmentCardiovascular Disease (CVD) / Heart Diseases / Heart Failure, Unspecified1
4CompletedTreatmentHeart Failure, Unspecified2
4CompletedTreatmentRight Heart Failure / Tricuspid valve incompetence1
4Not Yet RecruitingTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1
4RecruitingTreatmentCongestive Heart Failure (CHF)1
4RecruitingTreatmentDecompensated Heart Failure / Hyponatremias1
4RecruitingTreatmentHeart Failure, Unspecified / Hyponatremias1
4TerminatedTreatmentHeart Failure With Hyponatremia1
4TerminatedTreatmentHyponatremias1
4Unknown StatusTreatmentAscites / Hyponatremias1
4Unknown StatusTreatmentHyponatremia and Extracellular Fluid in Cirrhotic1
4WithdrawnPreventionHeart Failure, Unspecified1
Not AvailableActive Not RecruitingTreatmentAutosomal Dominant Polycystic Kidney Disease (ADPKD)1
Not AvailableActive Not RecruitingTreatmentCongestive Heart Failure (CHF)1
Not AvailableRecruitingNot AvailableAutosomal Dominant Polycystic Kidney Disease (ADPKD)1
Not AvailableRecruitingNot AvailableSafety1
Not AvailableRecruitingTreatmentCystine renal calculi1
Not AvailableTerminatedNot AvailableBrain Injury / Hyponatremias1
Not AvailableTerminatedTreatmentHyponatremias / SIADH1
Not AvailableUnknown StatusNot AvailableNon-Hyponatremia / Non-SIADH Hyponatremia / SIADH1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Kit
TabletOral15 mg
TabletOral15 mg/1
TabletOral30 mg/1
TabletOral30 mg
TabletOral60 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5258510No1993-11-022010-11-02Us
US5753677No1998-05-192020-05-19Us
US8501730No2013-08-062026-09-01Us
US5972882No1999-10-262018-12-14Us

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

Taxonomy

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
Benzanilide / Benzazepine / Benzamide / O-toluamide / Toluamide / Benzoic acid or derivatives / Benzoyl / Azepine / Toluene / Aryl chloride
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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
Human
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
Human
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
Human
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 December 12, 2018 07:17