Tolvaptan

Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V₂) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.^[9] Tolvaptan, as Jynarque, was granted approval for medical use in the United States in April 2018.^[10]

Tolvaptan

Clinical data
Trade names	Samsca, Jinarc, Jynarque, others
Other names	OPC-41061
AHFS/Drugs.com	Monograph
MedlinePlus	a609033
License data	US DailyMed: Tolvaptan
Pregnancy category	UK: Contraindicated
Routes of administration	By mouth
ATC code	C03XA01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] UK: POM (Prescription only)[2][3] US: ℞-only[4][5] EU: Rx-only[6][7]
Pharmacokinetic data
Bioavailability	Unknown (40% absorbed)
Protein binding	99%
Metabolism	Liver (CYP3A4-mediated)[8]
Elimination half-life	12 hours (terminal)
Identifiers
IUPAC name N-(4-{[(5R)-7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide
CAS Number	150683-30-0 N
PubChem CID	216237
IUPHAR/BPS	2226
DrugBank	DB06212 Y
ChemSpider	187438 Y
UNII	21G72T1950
KEGG	D01213
ChEBI	CHEBI:32246
ChEMBL	ChEMBL344159 Y
CompTox Dashboard (EPA)	DTXSID3048780
ECHA InfoCard	100.219.212
Chemical and physical data
Formula	C26H25ClN2O3
Molar mass	448.95 g·mol−1
3D model (JSmol)	Interactive image
SMILES Cc1ccccc1C(=O)Nc2cc(C)c(cc2)C(=O)N3c4ccc(Cl)cc4[C@H](O)CCC3
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) Y Key:GYHCTFXIZSNGJT-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

The U.S. Food and Drug Administration (FDA) granted tolvaptan a fast track designation for clinical trials investigating its use for the treatment of polycystic kidney disease.^[11] The FDA granted Jynarque an orphan drug designation in April 2012, for the treatment of autosomal dominant polycystic kidney disease.^[12]

Tolvaptan is available as a generic medication.^[13][14]

Medical uses

Tolvaptan (Samsca) is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.^[15]

Tolvaptan (Jynarque) is indicated for slow kidney-function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).^[16]

Tolvaptan phosphate is a prodrug of tolvaptan, developed for intravenous administration. Tolvaptan phosphate is converted into the active drug tolvaptan in the human body following administration.^[17]

Side effects

The FDA has determined that tolvaptan should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver failure.^[18] When using to treat hyponatremia, it may cause too rapid correction of hyponatremia resulting in fatal osmotic demyelination syndrome.^[19]

Pharmacology

Tolvaptan is a selective vasopressin V₂ receptor antagonist.^[15][16]

Chemistry

Tolvaptan is a racemate, a 1:1 mixture of the following two enantiomers:^[20]

Enantiomers of tolvaptan
(R)-Tolvaptan CAS number: 331947-66-1	(S)-Tolvaptan CAS number: 331947-44-5