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Identification
NameTolvaptan
Accession NumberDB06212
TypeSmall Molecule
GroupsApproved
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
Samsca
External Identifiers
  • OPC-41061
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Samscatablet15 mg/1oralOtsuka America Pharmaceutical Inc.2009-05-19Not applicableUs
Samscatablet60 mgoralOtsuka Pharmaceutical Co LtdNot applicableNot applicableCanada
Samscatablet30 mgoralOtsuka Pharmaceutical Co Ltd2011-09-22Not applicableCanada
Samscatablet15 mgoralOtsuka Pharmaceutical Co Ltd2011-09-22Not applicableCanada
Samscatablet30 mg/1oralOtsuka America Pharmaceutical Inc.2009-05-19Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
JinarcOtsuka Pharmaceutical Co Ltd
SaltsNot Available
Categories
UNII21G72T1950
CAS number150683-30-0
WeightAverage: 448.941
Monoisotopic: 448.155370383
Chemical FormulaC26H25ClN2O3
InChI KeyInChIKey=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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as n-phenylbenzamides. These are benzamides that are N-linked to a phenyl group via the carboxamide group.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassBenzamides
Direct ParentN-phenylbenzamides
Alternative Parents
Substituents
  • N-phenylbenzamide
  • Benzazepine
  • N-arylamide
  • Aminobenzoic acid or derivatives
  • Benzoic acid or derivatives
  • Aminotoluene
  • Benzoyl
  • Toluene
  • Chlorobenzene
  • Azepine
  • Aryl halide
  • Aryl chloride
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Secondary alcohol
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationTreatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and cirrhosis.
PharmacodynamicsUrine 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 actionTolvaptan 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.
Related Articles
AbsorptionTmax, 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 binding99% bound
Metabolism

Metabolism exclusively by CYP3A4 enzyme in the liver. Metabolites are inactive.

Route of eliminationFecal- very little renal elimination (<1% is excreted unchanged in the urine)
Half lifeTerminal half life, oral dose = 12 hours.
Clearance

4 mL/min/kg (post-oral dosing).

ToxicityThe 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral
Tabletoral15 mg/1
Tabletoral15 mg
Tabletoral30 mg
Tabletoral30 mg/1
Tabletoral60 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5258510 No1993-11-022010-11-02Us
US5753677 No2000-05-192020-05-19Us
US8501730 No2006-09-012026-09-01Us
Properties
StateSolid
Experimental PropertiesNot 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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot 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
ATC CodesC03XA01
AHFS Codes
  • 40:28.28
PDB EntriesNot Available
FDA labelDownload (468 KB)
MSDSDownload (103 KB)
Interactions
Drug Interactions
Drug
AmilorideTolvaptan may increase the hyperkalemic activities of Amiloride.
AprepitantThe serum concentration of Tolvaptan can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of Tolvaptan can be increased when it is combined with Atazanavir.
Azilsartan medoxomilTolvaptan may increase the hyperkalemic activities of Azilsartan medoxomil.
BenazeprilTolvaptan may increase the hyperkalemic activities of Benazepril.
BexaroteneThe serum concentration of Tolvaptan can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of Tolvaptan can be increased when it is combined with Boceprevir.
BosentanThe serum concentration of Tolvaptan can be decreased when it is combined with Bosentan.
CandesartanTolvaptan may increase the hyperkalemic activities of Candesartan.
CaptoprilTolvaptan may increase the hyperkalemic activities of Captopril.
CarbamazepineThe serum concentration of Tolvaptan can be decreased when it is combined with Carbamazepine.
CeritinibThe serum concentration of Tolvaptan can be increased when it is combined with Ceritinib.
CilazaprilTolvaptan may increase the hyperkalemic activities of Cilazapril.
ClarithromycinThe serum concentration of Tolvaptan can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of Tolvaptan can be increased when it is combined with Cobicistat.
ConivaptanThe serum concentration of Tolvaptan can be increased when it is combined with Conivaptan.
CrizotinibThe serum concentration of Tolvaptan can be increased when it is combined with Crizotinib.
DabrafenibThe serum concentration of Tolvaptan can be decreased when it is combined with Dabrafenib.
DarunavirThe serum concentration of Tolvaptan can be increased when it is combined with Darunavir.
DasatinibThe serum concentration of Tolvaptan can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Tolvaptan can be decreased when it is combined with Deferasirox.
DelavirdineThe serum concentration of Tolvaptan can be increased when it is combined with Delavirdine.
DesmopressinThe therapeutic efficacy of Desmopressin can be decreased when used in combination with Tolvaptan.
DigoxinThe serum concentration of Digoxin can be increased when it is combined with Tolvaptan.
DiltiazemThe serum concentration of Tolvaptan can be increased when it is combined with Diltiazem.
DronedaroneThe serum concentration of Tolvaptan can be increased when it is combined with Dronedarone.
EnalaprilTolvaptan may increase the hyperkalemic activities of Enalapril.
EnalaprilatTolvaptan may increase the hyperkalemic activities of Enalaprilat.
EnzalutamideThe serum concentration of Tolvaptan can be decreased when it is combined with Enzalutamide.
EplerenoneTolvaptan may increase the hyperkalemic activities of Eplerenone.
EprosartanTolvaptan may increase the hyperkalemic activities of Eprosartan.
ErythromycinThe serum concentration of Tolvaptan can be increased when it is combined with Erythromycin.
FluconazoleThe serum concentration of Tolvaptan can be increased when it is combined with Fluconazole.
FosamprenavirThe serum concentration of Tolvaptan can be increased when it is combined with Fosamprenavir.
FosaprepitantThe serum concentration of Tolvaptan can be increased when it is combined with Fosaprepitant.
FosinoprilTolvaptan may increase the hyperkalemic activities of Fosinopril.
FosphenytoinThe serum concentration of Tolvaptan can be decreased when it is combined with Fosphenytoin.
Fusidic AcidThe serum concentration of Tolvaptan can be increased when it is combined with Fusidic Acid.
IdelalisibThe serum concentration of Tolvaptan can be increased when it is combined with Idelalisib.
ImatinibThe serum concentration of Tolvaptan can be increased when it is combined with Imatinib.
IndinavirThe serum concentration of Tolvaptan can be increased when it is combined with Indinavir.
IrbesartanTolvaptan may increase the hyperkalemic activities of Irbesartan.
IsavuconazoniumThe serum concentration of Tolvaptan can be increased when it is combined with Isavuconazonium.
ItraconazoleThe serum concentration of Tolvaptan can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of Tolvaptan can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of Tolvaptan can be increased when it is combined with Ketoconazole.
LisinoprilTolvaptan may increase the hyperkalemic activities of Lisinopril.
LosartanTolvaptan may increase the hyperkalemic activities of Losartan.
LuliconazoleThe serum concentration of Tolvaptan can be increased when it is combined with Luliconazole.
MifepristoneThe serum concentration of Tolvaptan can be increased when it is combined with Mifepristone.
MitotaneThe serum concentration of Tolvaptan can be decreased when it is combined with Mitotane.
MoexiprilTolvaptan may increase the hyperkalemic activities of Moexipril.
NefazodoneThe serum concentration of Tolvaptan can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Tolvaptan can be increased when it is combined with Nelfinavir.
NilotinibThe serum concentration of Tolvaptan can be increased when it is combined with Nilotinib.
OlmesartanTolvaptan may increase the hyperkalemic activities of Olmesartan.
PalbociclibThe serum concentration of Tolvaptan can be increased when it is combined with Palbociclib.
PerindoprilTolvaptan may increase the hyperkalemic activities of Perindopril.
PhenobarbitalThe serum concentration of Tolvaptan can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Tolvaptan can be decreased when it is combined with Phenytoin.
PosaconazoleThe serum concentration of Tolvaptan can be increased when it is combined with Posaconazole.
PrimidoneThe serum concentration of Tolvaptan can be decreased when it is combined with Primidone.
QuinaprilTolvaptan may increase the hyperkalemic activities of Quinapril.
RamiprilTolvaptan may increase the hyperkalemic activities of Ramipril.
RanolazineThe serum concentration of Tolvaptan can be increased when it is combined with Ranolazine.
RifabutinThe serum concentration of Tolvaptan can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Tolvaptan can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Tolvaptan can be decreased when it is combined with Rifapentine.
RitonavirThe serum concentration of Tolvaptan can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Tolvaptan can be increased when it is combined with Saquinavir.
SiltuximabThe serum concentration of Tolvaptan can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Tolvaptan can be increased when it is combined with Simeprevir.
Sodium ChlorideThe risk or severity of adverse effects can be increased when Sodium Chloride is combined with Tolvaptan.
SpironolactoneTolvaptan may increase the hyperkalemic activities of Spironolactone.
St. John's WortThe serum concentration of Tolvaptan can be decreased when it is combined with St. John&#39;s Wort.
StiripentolThe serum concentration of Tolvaptan can be increased when it is combined with Stiripentol.
TelaprevirThe serum concentration of Tolvaptan can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Tolvaptan can be increased when it is combined with Telithromycin.
TelmisartanTolvaptan may increase the hyperkalemic activities of Telmisartan.
TesmilifeneThe serum concentration of Tolvaptan can be decreased when it is combined with Tesmilifene.
TocilizumabThe serum concentration of Tolvaptan can be decreased when it is combined with Tocilizumab.
TrandolaprilTolvaptan may increase the hyperkalemic activities of Trandolapril.
TriamtereneTolvaptan may increase the hyperkalemic activities of Triamterene.
ValsartanTolvaptan may increase the hyperkalemic activities of Valsartan.
VerapamilThe serum concentration of Tolvaptan can be increased when it is combined with Verapamil.
VoriconazoleThe serum concentration of Tolvaptan can be increased when it is combined with Voriconazole.
Food InteractionsNot 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
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 behaviors, including affiliation and attachment.
Gene Name:
AVPR1A
Uniprot ID:
P37288
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
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
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
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 ]
Comments
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Drug created on March 19, 2008 10:17 / Updated on August 24, 2016 01:52