Isocarboxazid

Identification

Summary

Isocarboxazid is a monoamine oxidase inhibitor used to treat enduring and debilitating symptoms of depression following inadequate clinical response to other antidepressant drugs.

Brand Names
Marplan
Generic Name
Isocarboxazid
DrugBank Accession Number
DB01247
Background

Isocarboxazid has the formula 1-benzyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine-isocarboxazid. It is a monoamine oxidase inhibitor.2 It is used in the treatment of major depression, dysthymic disorder, atypical disorder, panic disorder and the phobic disorders.4 It was first introduced by Roche pharmaceuticals, further developed by Validus pharms Inc and first FDA approved as a prescription drug on July 1st, 1959.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 231.2505
Monoisotopic: 231.100776675
Chemical Formula
C12H13N3O2
Synonyms
  • Isocarboxazid
  • Isocarboxazida
  • Isocarboxazide
  • Isocarboxazidum
External IDs
  • RO 5-0831
  • RO-5-0831

Pharmacology

Indication

Isocarboxazid is indicated for the treatment of the enduring and debilitating symptoms of depression that have not responded to other antidepressant drugs.7 Depression is a common but serious mood disorder. The patient will present changes in its feelings, thoughts, and ability to handle everyday activities. For a mood disorder to be considered as depression, the symptoms should be present for at least two weeks.8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofDepression••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

In vivo and in vitro studies demonstrated isocarboxazid-driven inhibition of MAO in the brain, heart, and liver. The reduced MAO activity, caused by isocarboxazid, results in an increased concentration of serotonin, epinephrine, norepinephrine, and dopamine in storage sites throughout the central nervous system (CNS) and sympathetic nervous system. The increase of one or more monoamines is the basis for the antidepressant activity of MAO inhibitors like isocarboxazid.1

Mechanism of action

Isocarboxazid works by irreversibly blocking the action of monoamine oxidases (MAO) in the nervous system. MAO subtypes A and B are involved in the metabolism of serotonin and catecholamine neurotransmitters such as epinephrine, norepinephrine, and dopamine. Isocarboxazid, as a nonselective MAO inhibitor, binds irreversibly to monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B).1 Isocarboxacid, like other monoamine oxidase inhibitors, are unique psychopharmacological agents whose clinical effect is related to the direct action of the monoamine oxidases to transform them into reactive metabolites.5

TargetActionsOrganism
AAmine oxidase [flavin-containing] A
inhibitor
Humans
AAmine oxidase [flavin-containing] B
inhibitor
Humans
Absorption

The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs are readily absorbed by the GI tract, present a low bioavailability and reach peak concentrations in 1-2 hours.5

Volume of distribution

Not Available

Protein binding

The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs present a very high protein binding percentage.5

Metabolism

The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs are rapidly metabolized by acetylation in the liver.5 As part of the metabolism, hippuric acid is a major metabolite.6

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Route of elimination

Most of the eliminated dose is found in the urine, accounting for the 42.5% of the administered dose after 24 hours. From this amount, 75% of the renally eliminated drug is in the form of hippuric acid. Another section of the eliminated dose is observed through the intestinal tract and it accounts for 22% of the administered dose after 24 hours.3

Half-life

The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. The isocarboxazid half-life is of little interest as it is an irreversible monoamine oxidase inhibitor.6 These drugs present a very short half-life of 1.5-4 hours due to rapid hepatic metabolism.5

Clearance

Not Available

Adverse Effects
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Toxicity

Long-term toxicity studies to evaluate the carcinogenic, mutagenic and fertility impairment potential have not been conducted.Label

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.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when Isocarboxazid is combined with 1,2-Benzodiazepine.
AbaloparatideIsocarboxazid may increase the orthostatic hypotensive activities of Abaloparatide.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Isocarboxazid is combined with Abciximab.
AcarboseIsocarboxazid may increase the hypoglycemic activities of Acarbose.
AcebutololIsocarboxazid may increase the hypotensive activities of Acebutolol.
Food Interactions
  • Avoid alcohol. The official product labeling suggests avoiding the use of CNS depressants.
  • Avoid tyramine-containing foods and supplements. Foods that contain tyramine include yogurt, aged cheese, ripe bananas, wine, and sourdough bread.
  • Limit caffeine intake.

Products

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International/Other Brands
Enerzer (Takeda) / Isocarboxazid (Alliance)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MarplanTablet10 mg/1OralValidus Pharmaceuticals LLC1959-07-01Not applicableUS flag
MarplanTablet10 mg/1OralMediLink A/S2018-12-20Not applicableUS flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
MarplanIsocarboxazid (10 mg/1)TabletOralMediLink A/S2018-12-20Not applicableUS flag

Categories

ATC Codes
N06AF01 — Isocarboxazid
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzene and substituted derivatives. These are aromatic compounds containing one monocyclic ring system consisting of benzene.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Not Available
Direct Parent
Benzene and substituted derivatives
Alternative Parents
Isoxazoles / Heteroaromatic compounds / Carboxylic acid hydrazides / Oxacyclic compounds / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Aromatic heteromonocyclic compound / Azacycle / Azole / Carboxylic acid derivative / Carboxylic acid hydrazide / Heteroaromatic compound / Hydrocarbon derivative / Isoxazole / Monocyclic benzene moiety / Organic nitrogen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
34237V843T
CAS number
59-63-2
InChI Key
XKFPYPQQHFEXRZ-UHFFFAOYSA-N
InChI
InChI=1S/C12H13N3O2/c1-9-7-11(15-17-9)12(16)14-13-8-10-5-3-2-4-6-10/h2-7,13H,8H2,1H3,(H,14,16)
IUPAC Name
N'-benzyl-5-methyl-1,2-oxazole-3-carbohydrazide
SMILES
CC1=CC(=NO1)C(=O)NNCC1=CC=CC=C1

References

General References
  1. Kennedy SH, Piran N, Warsh JJ, Prendergast P, Mainprize E, Whynot C, Garfinkel PE: A trial of isocarboxazid in the treatment of bulimia nervosa. J Clin Psychopharmacol. 1988 Dec;8(6):391-6. [Article]
  2. BARBER JM, MURPHY FM, CHEESEMAN EA: A clinical trial of isocarboxazid ('marplan') in angina pectoris. Br Heart J. 1962 Mar;24:192-4. [Article]
  3. SCHWARTZ MA: The metabolism of isocarboxazid (marplan) in the rat. J Pharmacol Exp Ther. 1960 Oct;130:157-65. [Article]
  4. Institute of Medicine (US) Council on Health Care Technology (1994). Medical Technology Assessment Directory (2nd ed.). American Medical Association Drug Evaluation.
  5. Owens D. (2010). Companion to psychiatric studies (8th ed.). Elsevier.
  6. Schatzberg A. and Nemeroff C. (2009). The american psychiatric publishing textbook of psychopharmacology (4th ed.). American Psychiatric Publishing Inc..
  7. Validus pharma news [Link]
  8. National Institute of Mental Health [Link]
Human Metabolome Database
HMDB0015377
KEGG Drug
D02580
PubChem Compound
3759
PubChem Substance
46505330
ChemSpider
3628
BindingDB
163692
RxNav
6011
ChEBI
93635
ChEMBL
CHEMBL1201168
ZINC
ZINC000000001587
Therapeutic Targets Database
DAP000577
PharmGKB
PA450101
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Isocarboxazid
FDA label
Download (56.5 KB)
MSDS
Download (186 KB)

Clinical Trials

Clinical Trials
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Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
0CompletedBasic ScienceAlzheimer's Disease (AD) / Healthy Volunteers (HV) / Molecular Imaging1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Oxford Pharmaceutical Services Inc.
  • Validus Pharmaceuticals
Dosage Forms
FormRouteStrength
TabletOral10 mg/1
Prices
Unit descriptionCostUnit
Marplan 10 mg tablet3.45USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)105-106 °C'MSDS'
boiling point (°C)394.5ºC at 760 mmHg'MSDS'
water solubilityVery slightly soluble in hot water'MSDS'
logP1.49'MSDS'
pKa10.4SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.224 mg/mLALOGPS
logP1.19ALOGPS
logP1.43Chemaxon
logS-3ALOGPS
pKa (Strongest Acidic)10.42Chemaxon
pKa (Strongest Basic)2.83Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area67.16 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity74.78 m3·mol-1Chemaxon
Polarizability24.15 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9783
Caco-2 permeable-0.5531
P-glycoprotein substrateNon-substrate0.6987
P-glycoprotein inhibitor INon-inhibitor0.9138
P-glycoprotein inhibitor IINon-inhibitor0.9716
Renal organic cation transporterNon-inhibitor0.8247
CYP450 2C9 substrateNon-substrate0.8471
CYP450 2D6 substrateNon-substrate0.8141
CYP450 3A4 substrateNon-substrate0.6057
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8885
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8518
Ames testAMES toxic0.5973
CarcinogenicityCarcinogens 0.5
BiodegradationNot ready biodegradable0.9227
Rat acute toxicity2.9486 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9209
hERG inhibition (predictor II)Non-inhibitor0.9069
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-MSsplash10-052f-9510000000-c11f3aaa62df1be7ea3f
GC-MS Spectrum - EI-BGC-MSsplash10-0006-9600000000-952a7c1093fe532d1df3
Mass Spectrum (Electron Ionization)MSsplash10-0006-9500000000-6ab30f52fc69889b3fa2
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0006-9210100010-78b2f412502a142509e6
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0006-9210100010-78b2f412502a142509e6
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-6690000000-4f07e03482d5dc853e20
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001l-6090000000-8d653cc99c1950dbec00
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-9200000000-44df4199b10094900be9
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-9530000000-0ce266c39817839ad2ad
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-9200000000-ba2867176067475620e3
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-052f-9300000000-0c6835498c567e3c4892
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-161.0686144
predicted
DarkChem Lite v0.1.0
[M-H]-162.1014144
predicted
DarkChem Lite v0.1.0
[M-H]-151.5676
predicted
DeepCCS 1.0 (2019)
[M+H]+161.5387144
predicted
DarkChem Lite v0.1.0
[M+H]+162.9655144
predicted
DarkChem Lite v0.1.0
[M+H]+153.9256
predicted
DeepCCS 1.0 (2019)
[M+Na]+160.6831144
predicted
DarkChem Lite v0.1.0
[M+Na]+162.0924144
predicted
DarkChem Lite v0.1.0
[M+Na]+160.01875
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Catalyzes the oxidative deamination of primary and some secondary amine such as neurotransmitters, with concomitant reduction of oxygen to hydrogen peroxide and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues (PubMed:18391214, PubMed:20493079, PubMed:24169519, PubMed:8316221). Preferentially oxidizes serotonin (PubMed:20493079, PubMed:24169519). Also catalyzes the oxidative deamination of kynuramine to 3-(2-aminophenyl)-3-oxopropanal that can spontaneously condense to 4-hydroxyquinoline (By similarity)
Specific Function
aliphatic amine oxidase activity
Gene Name
MAOA
Uniprot ID
P21397
Uniprot Name
Amine oxidase [flavin-containing] A
Molecular Weight
59681.27 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. Thase ME, Trivedi MH, Rush AJ: MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 1995 May;12(3):185-219. [Article]
  3. Kettler R, Da Prada M, Burkard WP: Comparison of monoamine oxidase-A inhibition by moclobemide in vitro and ex vivo in rats. Acta Psychiatr Scand Suppl. 1990;360:101-2. [Article]
  4. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Catalyzes the oxidative deamination of primary and some secondary amines such as neurotransmitters, and exogenous amines including the tertiary amine, neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with concomitant reduction of oxygen to hydrogen peroxide and participates in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues (PubMed:11049757, PubMed:11134050, PubMed:20493079, PubMed:8316221, PubMed:8665924). Preferentially degrades benzylamine and phenylethylamine (PubMed:11049757, PubMed:11134050, PubMed:20493079, PubMed:8316221, PubMed:8665924)
Specific Function
aliphatic amine oxidase activity
Gene Name
MAOB
Uniprot ID
P27338
Uniprot Name
Amine oxidase [flavin-containing] B
Molecular Weight
58762.475 Da
References
  1. Mason ST: Chronic administration of type A monoamine oxidase inhibitors increases duration of thiopentone anaesthesia in the rat. Physiol Behav. 1985 Aug;35(2):201-3. [Article]
  2. Kettler R, Da Prada M, Burkard WP: Comparison of monoamine oxidase-A inhibition by moclobemide in vitro and ex vivo in rats. Acta Psychiatr Scand Suppl. 1990;360:101-2. [Article]

Drug created at June 13, 2005 13:24 / Updated at February 21, 2021 18:51