View source for Chemistry:Tolvaptan

{{short description|Chemical compound}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 470611744
| IUPAC_name = ''N''-(4-{[(5''R'')-7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1''H''-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide
| image = (RS)-Tolvaptan Structural Formula V1.svg
| image2 = Tolvaptan ball-and-stick model.png

<!--Clinical data-->
| tradename = Samsca, Jinarc, Jynarque, others
| Drugs.com = {{drugs.com|monograph|tolvaptan}}
| MedlinePlus = a609033
| DailyMedID = Tolvaptan
| licence_US = Tolvaptan
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = C
| pregnancy_category = UK: Contraindicated 
| licence_EU = yes
| legal_AU = <!-- Unscheduled / S2 / S3 / S4  / S8 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Samsca 15 mg tablets - Summary of Product Characteristics (SmPC) | website=(emc) | url=https://www.medicines.org.uk/emc/product/6635/smpc | access-date=14 December 2020}}</ref><ref>{{cite web | title=Jinarc 15 mg tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=21 April 2020 | url=https://www.medicines.org.uk/emc/product/6849/smpc | access-date=14 December 2020}}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref>{{cite web | title=Jynarque- tolvaptan kit Jynarque- tolvaptan tablet | website=DailyMed | date=31 March 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3febc0a1-9e5a-4ce0-843d-210f21d862c4 | access-date=14 December 2020}}</ref><ref>{{cite web | title=Samsca- tolvaptan tablet | website=DailyMed | date=26 October 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5526617c-c7b9-4556-886d-729bbabbc566 | access-date=14 December 2020}}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Samsca EPAR">{{cite web | title=Samsca EPAR | website=[[Organization:European Medicines Agency|European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/samsca | access-date=14 December 2020}}</ref><ref name="Jinarc EPAR">{{cite web | title=Jinarc EPAR | website=[[Organization:European Medicines Agency|European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/jinarc | access-date=14 December 2020}}</ref>
| legal_status =  
| routes_of_administration = [[Medicine:Oral administration|By mouth]]
| ATC_prefix = C03
| ATC_suffix = XA01
| ATC_supplemental =

<!--Pharmacokinetic data-->
| bioavailability = Unknown (40% absorbed)
| protein_bound = 99%
| metabolism = [[Biology:Liver|Liver]] ([[Biology:CYP3A4|CYP3A4]]-mediated)<ref name=pk>{{cite journal  |vauthors=Shoaf S, Elizari M, Wang Z, etal | title = Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias | journal = J Cardiovasc Pharmacol Ther | volume = 10 | issue = 3 | pages = 165–71 | year = 2005 | pmid = 16211205 | doi = 10.1177/107424840501000304| s2cid = 39158242 | doi-access = free }}</ref>
| elimination_half-life = 12 hours (terminal)
| excretion =

<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 150683-30-0
| PubChem = 216237
| IUPHAR_ligand = 2226
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB06212
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 187438
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 21G72T1950
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 344159
| KEGG = D01213

<!--Chemical data-->
| C=26 | H=25 | Cl=1 | N=2 | O=3 
| smiles = Cc1ccccc1C(=O)Nc2cc(C)c(cc2)C(=O)N3c4ccc(Cl)cc4[C@H](O)CCC3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GYHCTFXIZSNGJT-UHFFFAOYSA-N
| synonyms = OPC-41061
}}

'''Tolvaptan''', sold under the brand name '''Samsca''' among others, is an [[Chemistry:Aquaretic|aquaretic]] drug that functions as a selective, competitive vasopressin receptor 2 (V<sub>2</sub>) antagonist used to treat [[Medicine:Hyponatremia|hyponatremia]] (low blood [[Chemistry:Sodium|sodium]] levels) associated with [[Medicine:Heart failure|congestive heart failure]], [[Medicine:Cirrhosis|cirrhosis]], and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.<ref>{{cite web | title=Drug Approval Package: Samsca (Tolvaptan) Tablets NDA #022275 | website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=21 July 2009 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022275s000TOC.cfm | access-date=15 August 2020}}</ref> Tolvaptan, as Jynarque, was granted approval for medical use in the United States in April 2018.<ref>{{cite web | title=Drug Approval Package: Jynarque (tolvaptan) | website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=8 June 2018 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/204441Orig1s000TOC.cfm | access-date=15 August 2020}}</ref>

The U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) granted tolvaptan a fast track designation for clinical trials investigating its use for the treatment of [[Medicine:Polycystic kidney disease|polycystic kidney disease]].<ref name="Otsuka">{{cite web |title=Otsuka Maryland Research Institute, Inc. Granted Fast Track Designation For Tolvaptan In PKD |url=https://www.medicalnewstoday.com/releases/38392.php |website=Medical News Today |publisher=Healthline Media UK Ltd |access-date=6 December 2018 }}</ref> The FDA granted Jynarque an [[Chemistry:Orphan drug|orphan drug]] designation in April 2012, for the treatment of autosomal dominant polycystic kidney disease.<ref>{{cite web | title=Tolvaptan Orphan Drug Designations and Approvals | website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=6 April 2012 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=20113473 | access-date=15 August 2020}}</ref>

Tolvaptan is available as a generic medication.<ref>{{cite web | title=Drugs@FDA: FDA-Approved Drugs | website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=211891 | access-date=15 August 2020}}</ref><ref>{{cite web | title=Tolvaptan Accord: Pending EC decision | website=[[Organization:European Medicines Agency|European Medicines Agency]] (EMA) | date=26 January 2023 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/tolvaptan-accord | access-date=28 January 2023}}</ref>

== Medical uses ==
Tolvaptan (Samsca) is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.<ref name="Samsca FDA label">{{cite web | title=Samsca- tolvaptan tablet | website=DailyMed | date=28 May 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5526617c-c7b9-4556-886d-729bbabbc566 | access-date=15 August 2020}}</ref>

Tolvaptan (Jynarque) is indicated for slow kidney-function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).<ref name="Jynarque FDA label">{{cite web | title=Jynarque- tolvaptan kit Jynarque- tolvaptan tablet | website=DailyMed | date=31 March 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3febc0a1-9e5a-4ce0-843d-210f21d862c4 | access-date=15 August 2020}}</ref>

[[Chemistry:Tolvaptan phosphate|Tolvaptan phosphate]] is a [[Chemistry:Prodrug|prodrug]] of tolvaptan, developed for intravenous administration.   Tolvaptan phosphate is converted into the active drug tolvaptan in the human body following administration.<ref>{{Cite press release | url = https://www.otsuka.co.jp/en/company/newsreleases/2022/20220328_1.html | title = Otsuka Obtains Approval in Japan for SAMTASU® for I.V. Infusion, a V2 -Receptor Antagonist for the Treatment of Cardiac Edema | date = March 28, 2022 | access-date = June 11, 2022}}</ref>

==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.<ref>"U.S. Food and Drug Administration." Samsca (Tolvaptan): Drug Safety Communication. N.p., 30 Apr. 2013. Web. 1 June 2014. <http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm>{{dead link|date=August 2020}}</ref> When using to treat hyponatremia, it may cause too rapid correction of [[Medicine:Hyponatremia|hyponatremia]] resulting in fatal [[Medicine:Central pontine myelinolysis|osmotic demyelination syndrome]].<ref>{{Cite book|title=Goodman & Gilman's the pharmacological basis of therapeutics|others=Brunton, Laurence L, Knollmann, Björn C, Hilal-Dandan, Randa|date=5 December 2017|isbn=9781259584732|edition=Thirteenth|location=New York|oclc=994570810}}</ref>

==Pharmacology==
Tolvaptan is a selective vasopressin V<sub>2</sub> receptor antagonist.<ref name="Samsca FDA label" /><ref name="Jynarque FDA label" />

== Chemistry ==
Tolvaptan is a racemate, a 1:1 mixture of the following two enantiomers:<ref name="Rote Liste">Rote Liste Service GmbH (Hrsg.): ''Rote Liste 2017 - Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte)''. Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, {{ISBN|978-3-946057-10-9}}, S. 222.</ref>
{| class="wikitable" style="text-align:center"
|- class="hintergrundfarbe6"
! colspan="2"| Enantiomers of tolvaptan
|-
| [[File:(R)-Tolvaptan Structural Formula V1.svg|250 px]]<br />(''R'')-Tolvaptan<br><small>CAS number: 331947-66-1</small>
| [[File:(S)-Tolvaptan Structural Formula V1.svg|250 px]]<br />(''S'')-Tolvaptan<br><small>CAS number: 331947-44-5</small>
|}

==References==
{{Reflist}}

== Further reading ==
*{{cite journal  |vauthors=Gheorghiade M, Niazi I, Ouyang J, etal | title = Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial | journal = Circulation | volume = 107 | issue = 21 | pages = 2690–6 | year = 2003 | pmid = 12742979| doi = 10.1161/01.CIR.0000070422.41439.04| doi-access = free }}

== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/tolvaptan | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Tolvaptan }}

{{Diuretics}}

[[Category:Diuretics]]
[[Category:Chloroarenes]]
[[Category:Secondary alcohols]]
[[Category:Benzazepanes]]
[[Category:Benzamides]]
[[Category:Benzanilides]]
[[Category:Orphan drugs]]

{{Sourceattribution|Tolvaptan}}