Conivaptan

Identification

Summary

Conivaptan is an antidiuretic hormone inhibitor used to raise serum sodium levels.

Brand Names

Vaprisol

Generic Name

Conivaptan

DrugBank Accession Number

DB00872

Background

Conivaptan is a non-peptide inhibitor of antidiuretic hormone (vasopressin). It was approved in 2004 for hyponatremia (low blood sodium levels) caused by syndrome of inappropriate antidiuretic hormone (SIADH). Conivaptan inhibits both isotypes of the vasopressin receptor (V1a and V2).

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Conivaptan (DB00872)

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Weight

Average: 498.5744
Monoisotopic: 498.205576096

Chemical Formula

C₃₂H₂₆N₄O₂

Synonyms

• 4'-((4,5-dihydro-2-methylimidazo(4,5-d)(1)benzazepin-6(1H)-yl)carbonyl)-2-biphenylcarboxanilide
• Conivaptan

External IDs

• YM 087
• YM-087

Pharmacology

Indication

For the treatment of euvolemic or hypervolemic hyponatremia (e.g. the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients.

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Associated Conditions

• Euvolemic Hyponatremia
• Hypervolemic Hyponatremia

Contraindications & Blackbox Warnings

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Pharmacodynamics

Conivaptan is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V_1A and V₂ receptors. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V₂ receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range by increasing permeability of the renal collecting ducts to water. Vasopressin also causes vasoconstriction through its actions on vascular _1A receptors. The predominant pharmacodynamic effect of conivaptan in the treatment of hyponatremia is through its V₂ antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water. Conivaptan's antagonist activity on V_1A receptors may also cause splanchnic vasodilation, resulting in possible hypotension or variceal bleeding in patients with cirrhosis. The pharmacodynamic effects of conivaptan include increased free water excretion (i.e., effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality.

Mechanism of action

Conivaptan is a dual AVP antagonist with nanomolar affinity for human arginine vasopressin V_1A and V₂ receptors in vitro. This antagonism occurs in the renal collecting ducts, resulting in aquaresis, or excretion of free water.

Target	Actions	Organism
AVasopressin V1a receptor	antagonist	Humans
AVasopressin V2 receptor	antagonist	Humans

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

99%

Metabolism

CYP3A4 is the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four metabolites have been identified. The pharmacological activity of the metabolites at V_1a and V₂ receptors ranged from approximately 3-50% and 50-100% that of conivaptan, respectively.

Route of elimination

Not Available

Half-life

5 hours

Clearance

Not Available

Adverse Effects

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Toxicity

Although no data on overdosage in humans are available, conivaptan has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of conivaptan, e.g. hypotension and thirst, occurred more frequently at these higher doses.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Conivaptan may increase the excretion rate of Abacavir which could result in a lower serum level and potentially a reduction in efficacy.
Abametapir	The serum concentration of Conivaptan can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Conivaptan can be increased when combined with Abatacept.
Abemaciclib	The metabolism of Conivaptan can be decreased when combined with Abemaciclib.
Abiraterone	The metabolism of Conivaptan can be decreased when combined with Abiraterone.
Acalabrutinib	The metabolism of Acalabrutinib can be decreased when combined with Conivaptan.
Acebutolol	The risk or severity of adverse effects can be increased when Conivaptan is combined with Acebutolol.
Aceclofenac	Conivaptan may increase the excretion rate of Aceclofenac which could result in a lower serum level and potentially a reduction in efficacy.
Acemetacin	The therapeutic efficacy of Conivaptan can be decreased when used in combination with Acemetacin.
Acenocoumarol	The serum concentration of Acenocoumarol can be increased when it is combined with Conivaptan.

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Food Interactions

No interactions found.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Conivaptan hydrochloride	75L57R6X36	168626-94-6	BTYHAFSDANBVMJ-UHFFFAOYSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Vaprisol	Liquid	5 mg/1mL	Conjunctival; Intravenous	Astellas Pharma US, Inc.	2007-03-02	2007-03-02
Vaprisol	Solution	20 mg/100mL	Intravenous	Astellas Pharma Inc	2008-10-08	2014-02-27
Vaprisol Dextrose In Plastic Container	Injection, solution	20 mg/100mL	Intravenous	Cumberland Pharmaceuticals	2008-10-08	Not applicable

Categories

ATC Codes

C03XA02 — Conivaptan

• C03XA — Vasopressin antagonists
• C03X — OTHER DIURETICS
• C03 — DIURETICS
• C — CARDIOVASCULAR SYSTEM

Drug Categories

• Antidiuretic Hormone Receptor Antagonists
• Cardiovascular Agents
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strong)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Diuretics
• Heterocyclic Compounds, Fused-Ring
• Hypotensive Agents
• Narrow Therapeutic Index Drugs
• Natriuretic Agents
• P-glycoprotein inhibitors

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as benzanilides. These are aromatic compounds containing an anilide group in which the carboxamide group is substituted with a benzene ring. They have the general structure RNC(=O)R', where R,R'= benzene.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Anilides

Direct Parent

Benzanilides

Alternative Parents

Biphenyls and derivatives / Benzazepines / Benzamides / Benzoyl derivatives / Azepines / Tertiary carboxylic acid amides / Imidazoles / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives

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Substituents

Aromatic heteropolycyclic compound / Azacycle / Azepine / Azole / Benzamide / Benzanilide / Benzazepine / Benzoic acid or derivatives / Benzoyl / Biphenyl / Carboxamide group / Carboxylic acid derivative / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Secondary carboxylic acid amide / Tertiary carboxylic acid amide

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

benzazepine (CHEBI:681850)

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

0NJ98Y462X

CAS number

210101-16-9

InChI Key

IKENVDNFQMCRTR-UHFFFAOYSA-N

InChI

InChI=1S/C32H26N4O2/c1-21-33-28-19-20-36(29-14-8-7-13-27(29)30(28)34-21)32(38)23-15-17-24(18-16-23)35-31(37)26-12-6-5-11-25(26)22-9-3-2-4-10-22/h2-18H,19-20H2,1H3,(H,33,34)(H,35,37)

IUPAC Name

N-(4-{4-methyl-3,5,9-triazatricyclo[8.4.0.0²,⁶]tetradeca-1(14),2(6),3,10,12-pentaene-9-carbonyl}phenyl)-2-phenylbenzamide

SMILES

CC1=NC2=C(CCN(C(=O)C3=CC=C(NC(=O)C4=CC=CC=C4C4=CC=CC=C4)C=C3)C3=CC=CC=C23)N1

References

General References

1. Ali F, Raufi MA, Washington B, Ghali JK: Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. Cardiovasc Drug Rev. 2007 Fall;25(3):261-79. [Article]
2. Mao ZL, Stalker D, Keirns J: Pharmacokinetics of conivaptan hydrochloride, a vasopressin V(1A)/V(2)-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4-day open-label study. Clin Ther. 2009 Jul;31(7):1542-50. doi: 10.1016/j.clinthera.2009.07.011. [Article]
3. Ghali JK, Farah JO, Daifallah S, Zabalawi HA, Zmily HD: Conivaptan and its role in the treatment of hyponatremia. Drug Des Devel Ther. 2009 Dec 29;3:253-68. [Article]

External Links

Human Metabolome Database

HMDB0015010

KEGG Drug

D07748

PubChem Compound

151171

PubChem Substance

46504533

ChemSpider

133239

BindingDB

85095

RxNav

302285

ChEBI

681850

ChEMBL

CHEMBL1755

ZINC

ZINC000012503187

Therapeutic Targets Database

DNC001525

PharmGKB

PA164742939

Guide to Pharmacology

GtP Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Conivaptan

FDA label

Download (145 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Euvolemia / Hyponatremia / Volume Overload	1
4	Completed	Treatment	Heart Failure	1
4	Terminated	Treatment	Hyponatremia	1
4	Withdrawn	Treatment	Heart Failure	1
3	Completed	Treatment	Hyponatremia	4
3	Terminated	Treatment	Acute Decompensated Heart Failure (ADHF) / Hyponatremia	1
3	Terminated	Treatment	Hyponatremia	1
3	Withdrawn	Treatment	Hyponatremia	1
2	Completed	Treatment	Chronic Heart Failure (CHF)	1
2	Completed	Treatment	Liver Cirrhosis	1

Pharmacoeconomics

Manufacturers

• Astellas pharma us inc

Packagers

• Astellas Pharma Inc.
• Baxter International Inc.

Dosage Forms

Form	Route	Strength
Liquid	Conjunctival; Intravenous	5 mg/1mL
Solution	Intravenous	20 mg/100mL
Injection, solution	Intravenous	20 mg/100mL

Prices

Unit description	Cost	Unit
Vaprisol 20 mg/100 ml bag	6.3USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US5723606	No	1998-03-03	2019-12-15

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Very slightly soluble (0.15 mg/mL at 23 °C)	Not Available
logP	6.3	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00175 mg/mL	ALOGPS
logP	5.23	ALOGPS
logP	5.44	ChemAxon
logS	-5.5	ALOGPS
pKa (Strongest Acidic)	11.14	ChemAxon
pKa (Strongest Basic)	6.23	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	78.09 Å2	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	150.83 m3·mol-1	ChemAxon
Polarizability	55.51 Å3	ChemAxon
Number of Rings	6	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	1.0
Blood Brain Barrier	+	0.9522
Caco-2 permeable	+	0.5291
P-glycoprotein substrate	Substrate	0.5919
P-glycoprotein inhibitor I	Inhibitor	0.6901
P-glycoprotein inhibitor II	Inhibitor	0.8429
Renal organic cation transporter	Non-inhibitor	0.6631
CYP450 2C9 substrate	Non-substrate	0.7671
CYP450 2D6 substrate	Non-substrate	0.7534
CYP450 3A4 substrate	Substrate	0.6602
CYP450 1A2 substrate	Inhibitor	0.7008
CYP450 2C9 inhibitor	Inhibitor	0.5368
CYP450 2D6 inhibitor	Non-inhibitor	0.6597
CYP450 2C19 inhibitor	Inhibitor	0.8477
CYP450 3A4 inhibitor	Inhibitor	0.9027
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.9043
Ames test	Non AMES toxic	0.6672
Carcinogenicity	Non-carcinogens	0.8831
Biodegradation	Not ready biodegradable	0.9584
Rat acute toxicity	2.5446 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9885
hERG inhibition (predictor II)	Inhibitor	0.8456

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	3	N/A	N/A	A29181
Ki (nM)	0.43	N/A	N/A	A29181

Details

Binding Properties1. Vasopressin V1a receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Vasopressin receptor activity

Specific Function

Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system. Has been involved in social behavi...

Gene Name

AVPR1A

Uniprot ID

P37288

Uniprot Name

Vasopressin V1a receptor

Molecular Weight

46799.105 Da

References

1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
2. Ali F, Raufi MA, Washington B, Ghali JK: Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. Cardiovasc Drug Rev. 2007 Fall;25(3):261-79. [Article]
3. Wada K, Matsukawa U, Fujimori A, Arai Y, Sudoh K, Sasamata M, Miyata K: A novel vasopressin dual V1A/V2 receptor antagonist, conivaptan hydrochloride, improves hyponatremia in rats with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Biol Pharm Bull. 2007 Jan;30(1):91-5. [Article]
4. Walter KA: Conivaptan: new treatment for hyponatremia. Am J Health Syst Pharm. 2007 Jul 1;64(13):1385-95. [Article]
5. Mao ZL, Stalker D, Keirns J: Pharmacokinetics of conivaptan hydrochloride, a vasopressin V(1A)/V(2)-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4-day open-label study. Clin Ther. 2009 Jul;31(7):1542-50. doi: 10.1016/j.clinthera.2009.07.011. [Article]
6. Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA, Smith N: Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab. 2006 Jun;91(6):2145-52. Epub 2006 Mar 7. [Article]
7. Annane D, Decaux G, Smith N: Efficacy and safety of oral conivaptan, a vasopressin-receptor antagonist, evaluated in a randomized, controlled trial in patients with euvolemic or hypervolemic hyponatremia. Am J Med Sci. 2009 Jan;337(1):28-36. doi: 10.1097/MAJ.0b013e31817b8148. [Article]
8. Ghali JK, Farah JO, Daifallah S, Zabalawi HA, Zmily HD: Conivaptan and its role in the treatment of hyponatremia. Drug Des Devel Ther. 2009 Dec 29;3:253-68. [Article]
9. Ali F, Guglin M, Vaitkevicius P, Ghali JK: Therapeutic potential of vasopressin receptor antagonists. Drugs. 2007;67(6):847-58. [Article]
10. Hoque MZ, Arumugham P, Huda N, Verma N, Afiniwala M, Karia DH: Conivaptan: promise of treatment in heart failure. Expert Opin Pharmacother. 2009 Sep;10(13):2161-9. doi: 10.1517/14656560903173237. [Article]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	11	N/A	N/A	A29181
Ki (nM)	0.36	N/A	N/A	A29181

Details

Binding Properties2. Vasopressin V2 receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Vasopressin receptor activity

Specific Function

Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption.

Gene Name

AVPR2

Uniprot ID

P30518

Uniprot Name

Vasopressin V2 receptor

Molecular Weight

40278.57 Da

References

1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
2. Wada K, Fujimori A, Matsukawa U, Arai Y, Sudoh K, Yatsu T, Sasamata M, Miyata K: Intravenous administration of conivaptan hydrochloride improves cardiac hemodynamics in rats with myocardial infarction-induced congestive heart failure. Eur J Pharmacol. 2005 Jan 10;507(1-3):145-51. Epub 2005 Jan 1. [Article]
3. Palm C, Pistrosch F, Herbrig K, Gross P: Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Am J Med. 2006 Jul;119(7 Suppl 1):S87-92. [Article]
4. Ali F, Raufi MA, Washington B, Ghali JK: Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. Cardiovasc Drug Rev. 2007 Fall;25(3):261-79. [Article]
5. Wada K, Matsukawa U, Fujimori A, Arai Y, Sudoh K, Sasamata M, Miyata K: A novel vasopressin dual V1A/V2 receptor antagonist, conivaptan hydrochloride, improves hyponatremia in rats with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Biol Pharm Bull. 2007 Jan;30(1):91-5. [Article]
6. Walter KA: Conivaptan: new treatment for hyponatremia. Am J Health Syst Pharm. 2007 Jul 1;64(13):1385-95. [Article]
7. Mao ZL, Stalker D, Keirns J: Pharmacokinetics of conivaptan hydrochloride, a vasopressin V(1A)/V(2)-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4-day open-label study. Clin Ther. 2009 Jul;31(7):1542-50. doi: 10.1016/j.clinthera.2009.07.011. [Article]
8. Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA, Smith N: Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab. 2006 Jun;91(6):2145-52. Epub 2006 Mar 7. [Article]
9. Annane D, Decaux G, Smith N: Efficacy and safety of oral conivaptan, a vasopressin-receptor antagonist, evaluated in a randomized, controlled trial in patients with euvolemic or hypervolemic hyponatremia. Am J Med Sci. 2009 Jan;337(1):28-36. doi: 10.1097/MAJ.0b013e31817b8148. [Article]
10. Ghali JK, Farah JO, Daifallah S, Zabalawi HA, Zmily HD: Conivaptan and its role in the treatment of hyponatremia. Drug Des Devel Ther. 2009 Dec 29;3:253-68. [Article]
11. Ali F, Guglin M, Vaitkevicius P, Ghali JK: Therapeutic potential of vasopressin receptor antagonists. Drugs. 2007;67(6):847-58. [Article]
12. Hoque MZ, Arumugham P, Huda N, Verma N, Afiniwala M, Karia DH: Conivaptan: promise of treatment in heart failure. Expert Opin Pharmacother. 2009 Sep;10(13):2161-9. doi: 10.1517/14656560903173237. [Article]

×

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Drug created on June 13, 2005 13:24 / Updated on April 03, 2021 09:39