Identification

Name
Conivaptan
Accession Number
DB00872  (APRD01302)
Type
Small Molecule
Groups
Approved, Investigational
Description

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).

Structure
Thumb
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
Product Ingredients
IngredientUNIICASInChI Key
Conivaptan hydrochloride75L57R6X36168626-94-6BTYHAFSDANBVMJ-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VaprisolSolution20 mg/100mLIntravenousAstellas Pharma Inc2008-10-082014-02-27Us
VaprisolLiquid5 mg/1mLConjunctival; IntravenousAstellas Pharma US, Inc.2007-03-022007-03-02Us
Vaprisol Dextrose In Plastic ContainerInjection, solution20 mg/100mLIntravenousCumberland Pharmaceuticals2008-10-08Not applicableUs
International/Other Brands
Vaprisol
Categories
UNII
0NJ98Y462X
CAS number
210101-16-9
Weight
Average: 498.5744
Monoisotopic: 498.205576096
Chemical Formula
C32H26N4O2
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

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.

Associated Conditions
Pharmacodynamics

Conivaptan is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V1A 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 V1A 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 V1A and V2 receptors in vitro. This antagonism occurs in the renal collecting ducts, resulting in aquaresis, or excretion of free water.

TargetActionsOrganism
AVasopressin V1a receptor
antagonist
Human
AVasopressin V2 receptor
antagonist
Human
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 V1a 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
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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Conivaptan can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Conivaptan can be decreased when combined with (S)-Warfarin.
3,5-diiodothyropropionic acidThe metabolism of Conivaptan can be decreased when combined with 3,5-diiodothyropropionic acid.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Conivaptan.
5-androstenedioneThe metabolism of Conivaptan can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Conivaptan can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Conivaptan can be decreased when combined with 6-O-benzylguanine.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Conivaptan.
AbirateroneThe metabolism of Conivaptan can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Conivaptan can be decreased when combined with Acalabrutinib.
Food Interactions
Not Available

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. [PubMed:17919259]
  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. [PubMed:19695403]
  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. [PubMed:20054444]
External Links
Human Metabolome Database
HMDB0015010
KEGG Drug
D01236
PubChem Compound
151171
PubChem Substance
46504533
ChemSpider
133239
BindingDB
85095
ChEBI
681850
ChEMBL
CHEMBL1755
Therapeutic Targets Database
DNC001525
PharmGKB
PA164742939
IUPHAR
2203
Guide to Pharmacology
GtP Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Conivaptan
ATC Codes
C03XA02 — Conivaptan
FDA label
Download (145 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHyponatremias / Kidney Diseases1
1CompletedNot AvailableHyponatremias / Liver Diseases1
1CompletedNot AvailableLiver Diseases1
1CompletedTreatmentSevere Traumatic Brain Injury1
2CompletedTreatmentChronic Heart Failure (CHF)1
2CompletedTreatmentLiver Cirrhosis1
2WithdrawnTreatmentCerebrovascular Accident, Acute / Edema of the cerebrum1
3CompletedTreatmentHyponatremias2
3TerminatedTreatmentAcute Decompensated Heart Failure (ADHF) / Hyponatremias1
3TerminatedTreatmentHyponatremias1
3WithdrawnTreatmentHyponatremias1
4CompletedTreatmentEuvolemia / Hyponatremias / Volume Overload1
4CompletedTreatmentHeart Failure, Unspecified1
4TerminatedTreatmentHyponatremias1
4WithdrawnTreatmentHeart Failure, Unspecified1
Not AvailableEnrolling by InvitationTreatmentEdema of the cerebrum / Intracerebral Hemorrhage / Strokes1
Not AvailableUnknown StatusNot AvailableHeart Failure, Unspecified1
Not AvailableWithdrawnTreatmentPulmonary Hypertension (PH) / Right Heart Failure1

Pharmacoeconomics

Manufacturers
  • Astellas pharma us inc
Packagers
  • Astellas Pharma Inc.
  • Baxter International Inc.
Dosage forms
FormRouteStrength
LiquidConjunctival; Intravenous5 mg/1mL
SolutionIntravenous20 mg/100mL
Injection, solutionIntravenous20 mg/100mL
Prices
Unit descriptionCostUnit
Vaprisol 20 mg/100 ml bag6.3USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5723606No1998-03-032019-12-15Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityVery slightly soluble (0.15 mg/mL at 23 °C)Not Available
logP6.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00175 mg/mLALOGPS
logP5.23ALOGPS
logP5.44ChemAxon
logS-5.5ALOGPS
pKa (Strongest Acidic)11.14ChemAxon
pKa (Strongest Basic)6.23ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area78.09 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity150.83 m3·mol-1ChemAxon
Polarizability55.51 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9522
Caco-2 permeable+0.5291
P-glycoprotein substrateSubstrate0.5919
P-glycoprotein inhibitor IInhibitor0.6901
P-glycoprotein inhibitor IIInhibitor0.8429
Renal organic cation transporterNon-inhibitor0.6631
CYP450 2C9 substrateNon-substrate0.7671
CYP450 2D6 substrateNon-substrate0.7534
CYP450 3A4 substrateSubstrate0.6602
CYP450 1A2 substrateInhibitor0.7008
CYP450 2C9 inhibitorInhibitor0.5368
CYP450 2D6 inhibitorNon-inhibitor0.6597
CYP450 2C19 inhibitorInhibitor0.8477
CYP450 3A4 inhibitorInhibitor0.9027
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9043
Ames testNon AMES toxic0.6672
CarcinogenicityNon-carcinogens0.8831
BiodegradationNot ready biodegradable0.9584
Rat acute toxicity2.5446 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9885
hERG inhibition (predictor II)Inhibitor0.8456
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
show 5 more
Substituents
Benzanilide / Biphenyl / Benzazepine / Benzamide / Benzoic acid or derivatives / Benzoyl / Azepine / Azole / Heteroaromatic compound / Imidazole
show 14 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
benzazepine (CHEBI:681850)

Targets

Details
1. Vasopressin V1a receptor
Kind
Protein
Organism
Human
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. [PubMed:11752352]
  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. [PubMed:17919259]
  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. [PubMed:17202666]
  4. Walter KA: Conivaptan: new treatment for hyponatremia. Am J Health Syst Pharm. 2007 Jul 1;64(13):1385-95. [PubMed:17592003]
  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. [PubMed:19695403]
  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. [PubMed:16522696]
  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. [PubMed:19057376]
  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. [PubMed:20054444]
  9. Ali F, Guglin M, Vaitkevicius P, Ghali JK: Therapeutic potential of vasopressin receptor antagonists. Drugs. 2007;67(6):847-58. [PubMed:17428103]
  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. [PubMed:19663609]
Details
2. Vasopressin V2 receptor
Kind
Protein
Organism
Human
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. [PubMed:11752352]
  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. [PubMed:15659304]
  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. [PubMed:16843091]
  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. [PubMed:17919259]
  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. [PubMed:17202666]
  6. Walter KA: Conivaptan: new treatment for hyponatremia. Am J Health Syst Pharm. 2007 Jul 1;64(13):1385-95. [PubMed:17592003]
  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. [PubMed:19695403]
  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. [PubMed:16522696]
  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. [PubMed:19057376]
  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. [PubMed:20054444]
  11. Ali F, Guglin M, Vaitkevicius P, Ghali JK: Therapeutic potential of vasopressin receptor antagonists. Drugs. 2007;67(6):847-58. [PubMed:17428103]
  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. [PubMed:19663609]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
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. [PubMed:17919259]
  2. Drug Interactions & Labeling - FDA [Link]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 08:41