U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry RACEMIC
Molecular Formula C26H25ClN2O3
Molecular Weight 448.941
Optical Activity ( + / - )
Defined Stereocenters 0 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TOLVAPTAN

SMILES

CC1=CC=CC=C1C(=O)NC2=CC(C)=C(C=C2)C(=O)N3CCCC(O)C4=C3C=CC(Cl)=C4

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

Molecular Formula C26H25ClN2O3
Molecular Weight 448.941
Charge 0
Count
Stereochemistry RACEMIC
Additional Stereochemistry No
Defined Stereocenters 0 / 1
E/Z Centers 0
Optical Activity ( + / - )

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
Vasopressin receptor antagonists in heart failure.
2003 Dec
Gateways to clinical trials.
2003 Nov
[Heart failure. Can vasopressin antagonists improve the prognosis?].
2003 Nov 27
Gateways to clinical trials.
2003 Sep
American Heart Association scientific sessions.
2004 Apr
Vasopressin receptor antagonists: will the "vaptans" fulfill their promise?
2004 Apr 28
Combination pharmacologic therapies for heart failure: what next after angiotensin-converting enzyme inhibitors and beta-blockers?
2005 Aug
New drugs for prevention, relief. How you might benefit if 3 medications win FDA approval.
2005 Oct
Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias.
2005 Sep
Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents.
2006 Apr
Vasopressin v(2) receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia.
2006 Apr 1
Gateways to clinical trials.
2006 Jan-Feb
Hyponatremia and heart failure--treatment considerations.
2006 Jan-Feb
Vasopressin receptor antagonists.
2006 Jun
[Diuretics].
2006 May
Tolvaptan: a selective vasopressin type 2 receptor antagonist in congestive heart failure.
2006 May
Vasopressin excess and hyponatremia.
2006 May
Gateways to clinical trials.
2006 Sep
[Vasopressin antagonists in treatment of hyponatremia].
2007 Aug
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
[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
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
Effects of nonpeptide vasopressin V2 antagonist tolvaptan in rats with heart failure.
2007 Nov 15
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.
Substance Class Chemical
Created
by admin
on Wed Jul 05 22:56:52 UTC 2023
Edited
by admin
on Wed Jul 05 22:56:52 UTC 2023
Record UNII
21G72T1950
Record Status Validated (UNII)
Record Version
  • Download
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 [VANDF]
Common Name English
TOLVAPTAN [JAN]
Common Name English
Tolvaptan [WHO-DD]
Common Name English
TOLVAPTAN [USAN]
Common Name English
Classification Tree Code System Code
LIVERTOX NBK548503
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
WHO-ATC C03XA01
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
EMA ASSESSMENT REPORTS SAMSCA (AUTHORIZED: INAPPROPRIATE ADH SYNDROME)
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
WHO-VATC QC03XA01
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
EMA ASSESSMENT REPORTS JINARC (AUTHORIZED: POLYCYSTIC KIDNEY, AUTOSOMAL DOMINANT)
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
FDA ORPHAN DRUG 347311
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
NDF-RT N0000193181
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
NCI_THESAURUS C2180
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
EU-Orphan Drug EU/3/13/1175
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
Code System Code Type Description
USAN
LL-16
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
EVMPD
SUB22755
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
SMS_ID
100000091683
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
DRUG BANK
DB06212
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
ChEMBL
CHEMBL344159
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
DAILYMED
21G72T1950
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
WIKIPEDIA
Tolvaptan
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
DRUG CENTRAL
4110
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
CAS
150683-30-0
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
EPA CompTox
DTXSID3048780
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
NCI_THESAURUS
C77082
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
MERCK INDEX
M10969
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY Merck Index
HSDB
8196
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
INN
7969
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
FDA UNII
21G72T1950
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
RXCUI
358257
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY RxNorm
PUBCHEM
216237
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
IUPHAR
2226
Created by admin on Wed Jul 05 22:56:52 UTC 2023 , Edited by admin on Wed Jul 05 22:56:52 UTC 2023
PRIMARY
Related Record Type Details
EXCRETED UNCHANGED
AMOUNT EXCRETED
FECAL
SALT/SOLVATE -> PARENT
ENANTIOMER -> RACEMATE
METABOLIC ENZYME -> SUBSTRATE
MAJOR
TRANSPORTER -> SUBSTRATE
ENANTIOMER -> RACEMATE
EXCRETED UNCHANGED
After oral administration of labeled tolvaptan the fraction of total radioactivity excreted in urine is 40 %. Less than 1% of the dose is excreted as unchanged tolvaptan.
AMOUNT EXCRETED
URINE
TARGET -> INHIBITOR
BINDER->LIGAND
BINDING
Related Record Type Details
METABOLITE -> PARENT
FECAL; PLASMA; URINE
METABOLITE -> PARENT
FECAL; URINE
METABOLITE -> PARENT
MICROSOMAL; PLASMA; URINE
METABOLITE INACTIVE -> PARENT
MAJOR
FECAL; MICROSOMAL; PLASMA; URINE
METABOLITE -> PARENT
FECAL; PLASMA; URINE
METABOLITE -> PARENT
FECAL; MICROSOMAL; PLASMA; URINE
METABOLITE -> PARENT
FECAL; MICROSOMAL; PLASMA; URINE
METABOLITE -> PARENT
FECAL; MICROSOMAL; PLASMA; URINE
METABOLITE -> PARENT
FECAL; PLASMA; URINE
METABOLITE -> PARENT
FECAL; MICROSOMAL; PLASMA; URINE
METABOLITE -> PARENT
FECAL; MICROSOMAL; PLASMA; URINE
METABOLITE -> PARENT
FECAL; URINE
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
NOAEL PHARMACOKINETIC
Biological Half-life PHARMACOKINETIC
NOAEL PHARMACOKINETIC
Volume of Distribution PHARMACOKINETIC