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Details

Stereochemistry RACEMIC
Molecular Formula C26H25ClN2O3
Molecular Weight 448.9422
Optical Activity ( + / - )
Defined Stereocenters 0 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TOLVAPTAN

SMILES

Cc1ccccc1C(=O)Nc2ccc(c(C)c2)C(=O)N3CCCC(c4cc(ccc43)Cl)O

InChI

InChIKey=GYHCTFXIZSNGJT-UHFFFAOYSA-N
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)

HIDE SMILES / InChI

Description
Curator's Comment:: Description was created based on several sources, including https://www.drugs.com/samsca.html

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. 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. Tolvaptan is sold under the trade names Samsca and Jinarc.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Samsca

Approved Use

Samsca® is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).

Launch Date

1.24260477E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
198 ng/mL
30 mg 1 times / day multiple, oral
dose: 30 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TOLVAPTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
125 ng/mL
15 mg single, oral
dose: 15 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLVAPTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
154 ng/mL
15 mg single, oral
dose: 15 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLVAPTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
1193 ng × h/mL
30 mg 1 times / day multiple, oral
dose: 30 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TOLVAPTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
683 ng × h/mL
15 mg single, oral
dose: 15 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLVAPTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
719 ng × h/mL
15 mg single, oral
dose: 15 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLVAPTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
3.3 h
30 mg 1 times / day multiple, oral
dose: 30 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TOLVAPTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
3.5 h
15 mg single, oral
dose: 15 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLVAPTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
3.2 h
15 mg single, oral
dose: 15 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TOLVAPTAN blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FED
Doses

Doses

DosePopulationAdverse events​
480 mg single, oral
Highest studied dose
healthy, 32 years (range: 20-51 years)
n = 6
Health Status: healthy
Age Group: 32 years (range: 20-51 years)
Sex: M+F
Population Size: 6
Sources:
Other AEs: Thirst, Urinary frequency...
Other AEs:
Thirst (6 patients)
Urinary frequency (6 patients)
Dry mouth (2 patients)
Headache NOS (2 patients)
Sources:
96 mg 1 times / day steady, oral (mean)
Dose: 96 mg, 1 times / day
Route: oral
Route: steady
Dose: 96 mg, 1 times / day
Sources:
unhealthy, 39 years
n = 961
Health Status: unhealthy
Condition: autosomal dominant polycystic kidney disease
Age Group: 39 years
Sex: M+F
Population Size: 961
Sources:
Disc. AE: Pollakiuria, Polyuria...
AEs leading to
discontinuation/dose reduction:
Pollakiuria (6.6%)
Polyuria (6.6%)
Nocturia (6.6%)
Sources:
300 mg 1 times / day multiple, oral
Highest studied dose
Dose: 300 mg, 1 times / day
Route: oral
Route: multiple
Dose: 300 mg, 1 times / day
Sources:
healthy, adult
1 mg single, intravenous
Dose: 1 mg
Route: intravenous
Route: single
Dose: 1 mg
Sources:
healthy, adult
n = 14
Health Status: healthy
Age Group: adult
Population Size: 14
Sources:
60 mg 1 times / day steady, oral (total)
Recommended
Dose: 60 mg, 1 times / day
Route: oral
Route: steady
Dose: 60 mg, 1 times / day
Sources:
unhealthy
Health Status: unhealthy
Condition: autosomal dominant polycystic kidney disease
Sources:
Other AEs: Liver injury...
AEs

AEs

AESignificanceDosePopulation
Dry mouth 2 patients
480 mg single, oral
Highest studied dose
healthy, 32 years (range: 20-51 years)
n = 6
Health Status: healthy
Age Group: 32 years (range: 20-51 years)
Sex: M+F
Population Size: 6
Sources:
Headache NOS 2 patients
480 mg single, oral
Highest studied dose
healthy, 32 years (range: 20-51 years)
n = 6
Health Status: healthy
Age Group: 32 years (range: 20-51 years)
Sex: M+F
Population Size: 6
Sources:
Thirst 6 patients
480 mg single, oral
Highest studied dose
healthy, 32 years (range: 20-51 years)
n = 6
Health Status: healthy
Age Group: 32 years (range: 20-51 years)
Sex: M+F
Population Size: 6
Sources:
Urinary frequency 6 patients
480 mg single, oral
Highest studied dose
healthy, 32 years (range: 20-51 years)
n = 6
Health Status: healthy
Age Group: 32 years (range: 20-51 years)
Sex: M+F
Population Size: 6
Sources:
Nocturia 6.6%
Disc. AE
96 mg 1 times / day steady, oral (mean)
Dose: 96 mg, 1 times / day
Route: oral
Route: steady
Dose: 96 mg, 1 times / day
Sources:
unhealthy, 39 years
n = 961
Health Status: unhealthy
Condition: autosomal dominant polycystic kidney disease
Age Group: 39 years
Sex: M+F
Population Size: 961
Sources:
Pollakiuria 6.6%
Disc. AE
96 mg 1 times / day steady, oral (mean)
Dose: 96 mg, 1 times / day
Route: oral
Route: steady
Dose: 96 mg, 1 times / day
Sources:
unhealthy, 39 years
n = 961
Health Status: unhealthy
Condition: autosomal dominant polycystic kidney disease
Age Group: 39 years
Sex: M+F
Population Size: 961
Sources:
Polyuria 6.6%
Disc. AE
96 mg 1 times / day steady, oral (mean)
Dose: 96 mg, 1 times / day
Route: oral
Route: steady
Dose: 96 mg, 1 times / day
Sources:
unhealthy, 39 years
n = 961
Health Status: unhealthy
Condition: autosomal dominant polycystic kidney disease
Age Group: 39 years
Sex: M+F
Population Size: 961
Sources:
Liver injury serious
60 mg 1 times / day steady, oral (total)
Recommended
Dose: 60 mg, 1 times / day
Route: oral
Route: steady
Dose: 60 mg, 1 times / day
Sources:
unhealthy
Health Status: unhealthy
Condition: autosomal dominant polycystic kidney disease
Sources:
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG


Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
yes [IC50 0.837 uM]
yes [IC50 15.9 uM]
weak (co-administration study)
Comment: administration with digoxin increased Digoxin Cmax and AUC by 30% and 20%, respectively
Page: 6,11
yes [IC50 27.2 uM]
yes [IC50 4.14 uM]
yes [IC50 41.5 uM]
yes [IC50 5.47 uM]
yes [IC50 50 uM]
yes [IC50 50 uM]
yes [IC50 50 uM]
yes [IC50 6.15 uM]
yes [IC50 7.965 uM]
yes [IC50 8.32 uM]
yes [IC50 >10 uM]
yes [IC50 >30 uM]
yes [Ki 34 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
yes
yes
yes (co-administration study)
Comment: administration with ketoconazole caused a 3.5-fold and 5-fold increase in tolvaptan Cmax and AUC, respectively; administration with rifmapin reduced Cmax and AUC of tolvaptan to 10 and 20%, respectively;
Page: 96.0
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Comparison of 60-day mortality in hospitalized heart failure patients with versus without hypothermia.
2006 Dec 1
Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.
2006 Jul
Vasopressin antagonists--progress and promise.
2006 Nov 16
Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.
2006 Nov 16
Gateways to clinical trials.
2006 Sep
AVP receptor antagonists as aquaretics: review and assessment of clinical data.
2006 Sep
Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial.
2007
Aquaretic agents: what's beyond the treatment of hyponatremia?
2007
Therapeutic potential of vasopressin receptor antagonists.
2007
Cerebral correlates of hyponatremia.
2007
[Vasopressin antagonists in treatment of hyponatremia].
2007 Aug
Pharmacokinetic and pharmacodynamic interaction between tolvaptan, a non-peptide AVP antagonist, and furosemide or hydrochlorothiazide.
2007 Aug
Effects of tolvaptan, an oral vasopressin V2 receptor antagonist, in hyponatremia.
2007 Aug
Tolvaptan, an oral vasopressin V2 receptor antagonist for heart failure?
2007 Dec
Clinical trials update from the European Society of Cardiology Congress in Vienna, 2007: PROSPECT, EVEREST, ARISE, ALOFT, FINESSE, Prague-8, CARESS in MI and ACUITY.
2007 Dec
Pharmacokinetics, pharmacodynamics, and safety of tolvaptan, a nonpeptide AVP antagonist, during ascending single-dose studies in healthy subjects.
2007 Dec
Diagnosis and management of hyponatremia in cancer patients.
2007 Dec
Aminocarbonylation route to tolvaptan.
2007 Dec 1
Recognition and treatment of hyponatremia in acutely ill hospitalized patients.
2007 Feb
Evaluation and management of hyponatremia: an emerging role for vasopressin receptor antagonists.
2007 Feb
Nephrogenic syndrome of inappropriate antidiuresis in adults: high phenotypic variability in men and women from a large pedigree.
2007 Feb
New agents for managing hyponatremia in hospitalized patients.
2007 Feb 1
Clinical trials update from the American Heart Association 2006: OAT, SALT 1 and 2, MAGIC, ABCD, PABA-CHF, IMPROVE-CHF, and percutaneous mitral annuloplasty.
2007 Jan
Role of vasopressin in rat distal colon function.
2007 Jan 15
[Arginine vasopressin antagonism--new treatment option in chronic heart failure].
2007 Jan 18
Gateways to clinical trials.
2007 Jan-Feb
Gateways to clinical trials.
2007 Jul-Aug
[Recent progress in vasopressin research on cardiovascular diseases].
2007 Jun
Vaptans: a promising therapy in the management of advanced cirrhosis.
2007 Jun
Arginine vasopressin receptor antagonists for heart failure: a winter climbing to the Everest's tip?
2007 Jun 5
Multicenter, randomized, double-blind, placebo-controlled study on the effect of oral tolvaptan on left ventricular dilation and function in patients with heart failure and systolic dysfunction.
2007 Jun 5
Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR-2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro-BNP for the evaluation of dyspnoea and THIS-diet.
2007 Jun-Jul
Gateways to clinical trials.
2007 Mar
Tolvaptan for hyponatremia.
2007 Mar 1
Tolvaptan for hyponatremia.
2007 Mar 1
Tolvaptan for hyponatremia.
2007 Mar 1
Tolvaptan for hyponatremia.
2007 Mar 1
Climbing the mountain of acute decompensated heart failure: the EVEREST Trials.
2007 Mar 28
Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials.
2007 Mar 28
Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial.
2007 Mar 28
What new drugs can nephrologists look forward to in the next year or two?
2007 May
Hyponatremia: current treatment strategies and the role of vasopressin antagonists.
2007 May
[Vasopressin V2-receptor antagonist, tolvaptan, for treatment of heart failure].
2007 May 28
Current issues for nurse practitioners: Hyponatremia.
2007 Nov
Hyponatremia and vasopressin antagonism in congestive heart failure.
2007 Nov
Effects of nonpeptide vasopressin V2 antagonist tolvaptan in rats with heart failure.
2007 Nov 15
Water in health and disease: new aspects of disturbances in water metabolism.
2007 Oct
V2 receptor antagonism with tolvaptan in heart failure.
2007 Oct
Tolvaptan, an orally active vasopressin V(2)-receptor antagonist - pharmacology and clinical trials.
2007 Spring
Polycystic kidney diseases: from molecular discoveries to targeted therapeutic strategies.
2008 Feb
Patents

Patents

Sample Use Guides

In Vivo Use Guide
The usual starting dose for Samsca (Tolvaptan) is 15 mg administered once daily without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium. Do not administer Samsca for more than 30 days to minimize the risk of liver injury
Route of Administration: Oral
In Vitro Use Guide
Curator's Comment:: Tolvaptan inhibits ERK-dependent cell proliferation, Cl⁻ secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin.
Tolvaptan caused a concentration-dependent inhibition of AVP-induced cAMP production with an apparent IC(50) of ∼10(-10) M.
Name Type Language
TOLVAPTAN
DASH   EMA EPAR   INN   JAN   MART.   MI   ORANGE BOOK   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
TOLVAPTAN [ORANGE BOOK]
Common Name English
OPC-41061
Code English
TOLVAPTAN [MART.]
Common Name English
JINARC
Brand Name English
SAMSCA
Brand Name English
JYNARQUE
Brand Name English
TOLVAPTAN [INN]
Common Name English
(+/-)-4'-((7-CHLORO-2,3,4,5-TETRAHYDRO-5-HYDROXY-1H-1-BENZAZEPIN-1-YL) CARBONYL)-O-TOLU-M-TOLUIDIDE
Common Name English
OPC-41061(TOLVAPTAN)
Code English
TOLVAPTAN [EMA EPAR]
Common Name English
BENZAMIDE, N-(4-((7-CHLORO-2,3,4,5-TETRAHYDRO-5-HYDROXY-1H-1-BENZAZEPIN-1-YL)CARBONYL)-3-METHYLPHENYL)-2-METHYL-
Systematic Name English
TOLVAPTAN [MI]
Common Name English
TOLVAPTAN [WHO-DD]
Common Name English
TOLVAPTAN [VANDF]
Common Name English
TOLVAPTAN [JAN]
Common Name English
TOLVAPTAN [USAN]
Common Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 347311
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
LIVERTOX 980
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
WHO-ATC C03XA01
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
EMA ASSESSMENT REPORTS SAMSCA (AUTHORIZED: INAPPROPRIATE ADH SYNDROME)
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
WHO-VATC QC03XA01
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
EMA ASSESSMENT REPORTS JINARC (AUTHORIZED: POLYCYSTIC KIDNEY, AUTOSOMAL DOMINANT)
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
NDF-RT N0000193181
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
NCI_THESAURUS C2180
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
EU-Orphan Drug EU/3/13/1175
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
Code System Code Type Description
EVMPD
SUB22755
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
DRUG BANK
DB06212
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
ChEMBL
CHEMBL344159
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
DRUG CENTRAL
4110
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
CAS
150683-30-0
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
EPA CompTox
150683-30-0
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
NCI_THESAURUS
C77082
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
MERCK INDEX
M10969
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY Merck Index
HSDB
8196
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
INN
7969
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
FDA UNII
21G72T1950
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
RXCUI
358257
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY RxNorm
PUBCHEM
216237
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY
IUPHAR
2226
Created by admin on Sat Jun 26 12:18:10 UTC 2021 , Edited by admin on Sat Jun 26 12:18:10 UTC 2021
PRIMARY