Tolvaptan

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Tolvaptan
(RS)-Tolvaptan Structural Formula V1.svg
Tolvaptan ball-and-stick model.png
Clinical data
Trade namesSamsca, Jinarc
SynonymsOPC-41061
AHFS/Drugs.comMonograph
MedlinePlusa609033
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityUnknown (40% absorbed)
Protein binding99%
MetabolismHepatic (CYP3A4-mediated)[1]
Elimination half-life12 hours (terminal)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard100.219.212 Edit this at Wikidata
Chemical and physical data
FormulaC26H25ClN2O3
Molar mass448.95 g·mol−1
3D model (JSmol)
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Tolvaptan (INN, trade names Samsca and Jinarc) is an aquaretic drug that functions as 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 (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolsama & Tolvat .

Tolvaptan was also in fast-track clinical trials[2] 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.[3] 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)[4]

Side effects[edit]

FDA has determined that the drug Samsca (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[5]

Chemistry[edit]

Tolvaptan is a racemate, a 1: 1 mixture of the following two enantiomers:[6]

Enantiomers of tolvaptan
(R)-Tolvaptan Structural Formula V1.svg
CAS number: 331947-66-1
(S)-Tolvaptan Structural Formula V1.svg
CAS number: 331947-44-5

References[edit]

  1. ^ 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.
  2. ^ Otsuka Maryland Research Institute, Inc.
  3. ^ 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.
  4. ^ Torres, Vicente E; Chapman, Arlene B; Devuyst, Olivier; Gansevoort, Ron T; Grantham, Jared J; Higashihara, Eiji; Perrone, Ronald D; Krasa, Holly B; Ouyang, John; Czerwiec, Frank S (2012). "Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease". New England Journal of Medicine. 367 (25): 2407. doi:10.1056/NEJMoa1205511. PMC 3760207. PMID 23121377.
  5. ^ "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>
  6. ^ 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.
  • 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.