Tolvaptan

Tolvaptan
Clinical data
Trade names	Samsca
Other names	N-{4-[(6R)-9-chloro-6-hydroxy-2-azabicyclo[5.4.0]undeca-8,10,12-triene-2-carbonyl]-3-methyl-phenyl}-2-methyl-benzamide
AHFS/Drugs.com	Monograph
MedlinePlus	a609033
License data	US FDA: Tolvaptan;
Routes of; administration	Oral
ATC code	C03XA01 (WHO) ;
Legal status
Legal status	US: WARNINGRx-only;
Pharmacokinetic data
Bioavailability	Unknown (40% absorbed)
Protein binding	99%
Metabolism	Hepatic (CYP3A4-mediated)
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 ;
PubChem CID	216237;
IUPHAR/BPS	2226;
ChemSpider	187438 ;
UNII	21G72T1950;
ChEMBL	ChEMBL344159 ;
CompTox Dashboard (EPA)	DTXSID3048780 ;
ECHA InfoCard	100.219.212
Chemical and physical data
Formula	C26H25ClN2O3
Molar mass	448.941 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(c1ccccc1C)Nc2ccc(c(c2)C)C(=O)N4c3ccc(Cl)cc3C(O)CCC4;
	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) ; Key:GYHCTFXIZSNGJT-UHFFFAOYSA-N ;
	(what is this?) (verify)

Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 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 on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is sold by MSN laboratories LTD under the trade name Tolvat & Tolsama and by SUN PHARMA under the trade name NATRISE. Tolvaptan is also in fast-track clinical trials^[3] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia (decreased blood levels of potassium) and without having an adverse effect on kidney function.^[4] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)^[5]

Chemistry

Chemical synthesis:^[6]

Side effects

The FDA has warned of potential liver injury with the drug.^[7]

References

^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
^ Shoaf S, Elizari M, Wang Z; et al. (2005). "Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias". J Cardiovasc Pharmacol Ther. 10 (3): 165–71. doi:10.1177/107424840501000304. PMID 16211205. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Otsuka Maryland Research Institute, Inc.
^ Gheorghiade M, Gattis W, O'Connor C; et al. (2004). "Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial". JAMA. 291 (16): 1963–71. doi:10.1001/jama.291.16.1963. PMID 15113814. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ (2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
^ Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.
^ 2013 MedPage Today http://www.medpagetoday.com/Nephrology/GeneralNephrology/37000

Gheorghiade M, Niazi I, Ouyang J; et al. (2003). "Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial". Circulation. 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04. PMID 12742979. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

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[FDA-AllBoxedWarnings-1] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.

[pk-2] Shoaf S, Elizari M, Wang Z; et al. (2005). "Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias". J Cardiovasc Pharmacol Ther. 10 (3): 165–71. doi:10.1177/107424840501000304. PMID 16211205. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

[3] Otsuka Maryland Research Institute, Inc.

[ACTIV-4] Gheorghiade M, Gattis W, O'Connor C; et al. (2004). "Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial". JAMA. 291 (16): 1963–71. doi:10.1001/jama.291.16.1963. PMID 15113814. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

[5] (2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease

[6] Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.

[7] 2013 MedPage Today http://www.medpagetoday.com/Nephrology/GeneralNephrology/37000

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