Isocarboxazid

Identification

Name

Isocarboxazid

Accession Number

DB01247

Description

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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Isocarboxazid (DB01247)

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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

Associated Conditions

• Depression

Contraindications & Blackbox Warnings

Learn about our commercial Contraindications & Blackbox Warnings data.

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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

Target	Actions	Organism
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

Hover over products below to view reaction partners

• Isocarboxazid
  • Hippuric acid

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

Learn about our commercial Adverse Effects data.

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Toxicity

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

Affected organisms

• Humans and other mammals

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
Unlock Additional Data
Abciximab	The risk or severity of bleeding and hemorrhage can be increased when Isocarboxazid is combined with Abciximab.
Acarbose	Isocarboxazid may increase the hypoglycemic activities of Acarbose.
Acebutolol	Isocarboxazid may increase the hypotensive activities of Acebutolol.
Aceclofenac	The risk or severity of hypertension can be increased when Isocarboxazid is combined with Aceclofenac.
Acemetacin	The risk or severity of hypertension can be increased when Isocarboxazid is combined with Acemetacin.
Acenocoumarol	The risk or severity of bleeding and hemorrhage can be increased when Isocarboxazid is combined with Acenocoumarol.
Acetazolamide	The risk or severity of adverse effects can be increased when Acetazolamide is combined with Isocarboxazid.
Acetohexamide	Isocarboxazid may increase the hypoglycemic activities of Acetohexamide.
Acetophenazine	The risk or severity of extrapyramidal symptoms can be increased when Isocarboxazid is combined with Acetophenazine.
Acetylsalicylic acid	The risk or severity of bleeding and hemorrhage can be increased when Isocarboxazid is combined with Acetylsalicylic acid.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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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

International/Other Brands

Enerzer (Takeda) / Isocarboxazid (Alliance)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Unlock Additional Data
Marplan	Tablet	10 mg/1	Oral	MediLink A/S	2018-12-20	Not applicable
Marplan	Tablet	10 mg/1	Oral	Validus Pharmaceuticals LLC	1959-07-01	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Marplan	Isocarboxazid (10 mg/1)	Tablet	Oral	MediLink A/S	2018-12-20	Not applicable

Categories

ATC Codes

N06AF01 — Isocarboxazid

• N06AF — Monoamine oxidase inhibitors, non-selective
• N06A — ANTIDEPRESSANTS
• N06 — PSYCHOANALEPTICS
• N — NERVOUS SYSTEM

Drug Categories

• Agents that produce hypertension
• Agents that reduce seizure threshold
• Antidepressive Agents
• Central Nervous System Agents
• Central Nervous System Depressants
• Drugs causing inadvertant photosensitivity
• Enzyme Inhibitors
• Hypotensive Agents
• Isoxazoles
• Monoamine Oxidase A Inhibitors for interaction with Monoamine Oxidase A substrates
• Monoamine Oxidase Inhibitors
• Monoamine Oxidase Inhibitors, Non-Selective
• Nervous System
• Photosensitizing Agents
• Psychoanaleptics
• Psychotropic Drugs
• Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
• Serotonin Agents
• Serotonin Modulators

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

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. [PubMed:3069879]
2. BARBER JM, MURPHY FM, CHEESEMAN EA: A clinical trial of isocarboxazid ('marplan') in angina pectoris. Br Heart J. 1962 Mar;24:192-4. [PubMed:13864836]
3. SCHWARTZ MA: The metabolism of isocarboxazid (marplan) in the rat. J Pharmacol Exp Ther. 1960 Oct;130:157-65. [PubMed:13749111]
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]

External Links

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

Phase	Status	Purpose	Conditions	Count
0	Completed	Basic Science	Alzheimer's Disease (AD) / Healthy Volunteers / Molecular Imaging	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

• Oxford Pharmaceutical Services Inc.
• Validus Pharmaceuticals

Dosage Forms

Form	Route	Strength
Tablet	Oral	10 mg/1

Prices

Unit description	Cost	Unit
Marplan 10 mg tablet	3.45USD	tablet

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

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	105-106 °C	'MSDS'
boiling point (°C)	394.5ºC at 760 mmHg	'MSDS'
water solubility	Very slightly soluble in hot water	'MSDS'
logP	1.49	'MSDS'
pKa	10.4	SANGSTER (1994)

Predicted Properties

Property	Value	Source
Water Solubility	0.224 mg/mL	ALOGPS
logP	1.19	ALOGPS
logP	1.43	ChemAxon
logS	-3	ALOGPS
pKa (Strongest Acidic)	12.02	ChemAxon
pKa (Strongest Basic)	3.12	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	67.16 Å2	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	74.78 m3·mol-1	ChemAxon
Polarizability	24.51 Å3	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	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	+	0.9783
Caco-2 permeable	-	0.5531
P-glycoprotein substrate	Non-substrate	0.6987
P-glycoprotein inhibitor I	Non-inhibitor	0.9138
P-glycoprotein inhibitor II	Non-inhibitor	0.9716
Renal organic cation transporter	Non-inhibitor	0.8247
CYP450 2C9 substrate	Non-substrate	0.8471
CYP450 2D6 substrate	Non-substrate	0.8141
CYP450 3A4 substrate	Non-substrate	0.6057
CYP450 1A2 substrate	Inhibitor	0.9107
CYP450 2C9 inhibitor	Non-inhibitor	0.9071
CYP450 2D6 inhibitor	Non-inhibitor	0.9231
CYP450 2C19 inhibitor	Non-inhibitor	0.9026
CYP450 3A4 inhibitor	Non-inhibitor	0.8885
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.8518
Ames test	AMES toxic	0.5973
Carcinogenicity	Carcinogens	0.5
Biodegradation	Not ready biodegradable	0.9227
Rat acute toxicity	2.9486 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9209
hERG inhibition (predictor II)	Non-inhibitor	0.9069

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
GC-MS Spectrum - EI-B	GC-MS	splash10-0006-9600000000-952a7c1093fe532d1df3
Mass Spectrum (Electron Ionization)	MS	splash10-0006-9500000000-6ab30f52fc69889b3fa2
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
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	Not Available
MS/MS Spectrum - , positive	LC-MS/MS	splash10-0006-9210100010-78b2f412502a142509e6

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Drug created on June 13, 2005 07:24 / Updated on July 14, 2020 04:58