Identification

Name
Isocarboxazid
Accession Number
DB01247  (APRD00701)
Type
Small Molecule
Groups
Approved
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.

Structure
Thumb
Synonyms
  • Isocarboxazida
  • Isocarboxazide
  • Isocarboxazidum
External IDs
RO 5-0831 / RO-5-0831
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MarplanTablet10 mg/1OralValidus Pharmaceuticals LLC1959-07-01Not applicableUs
International/Other Brands
Enerzer (Takeda) / Isocarboxazid (Alliance) / Marplan (Validus Pharm)
Categories
UNII
34237V843T
CAS number
59-63-2
Weight
Average: 231.2505
Monoisotopic: 231.100776675
Chemical Formula
C12H13N3O2
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

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
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
Human
AAmine oxidase [flavin-containing] B
inhibitor
Human
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]

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
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
DrugInteraction
2,5-Dimethoxy-4-ethylamphetamineIsocarboxazid may increase the hypertensive activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Isocarboxazid.
3,4-MethylenedioxyamphetamineThe therapeutic efficacy of 3,4-Methylenedioxyamphetamine can be increased when used in combination with Isocarboxazid.
4-Bromo-2,5-dimethoxyamphetamineThe therapeutic efficacy of 4-Bromo-2,5-dimethoxyamphetamine can be increased when used in combination with Isocarboxazid.
4-MethoxyamphetamineThe therapeutic efficacy of 4-Methoxyamphetamine can be increased when used in combination with Isocarboxazid.
5-methoxy-N,N-dimethyltryptamineThe metabolism of 5-methoxy-N,N-dimethyltryptamine can be decreased when combined with Isocarboxazid.
7-NitroindazoleThe therapeutic efficacy of 7-Nitroindazole can be increased when used in combination with Isocarboxazid.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineIsocarboxazid may increase the hypertensive activities of 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AbediterolThe risk or severity of adverse effects can be increased when Isocarboxazid is combined with Abediterol.
AcarboseIsocarboxazid may increase the hypoglycemic activities of Acarbose.
Food Interactions
  • Take without regard to meals, avoid tyramine, caffeine and alcohol.

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
ChEBI
93635
ChEMBL
CHEMBL1201168
Therapeutic Targets Database
DAP000577
PharmGKB
PA450101
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Isocarboxazid
ATC Codes
N06AF01 — Isocarboxazid
FDA label
Download (56.5 KB)
MSDS
Download (186 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedBasic ScienceAlzheimer's Disease (AD) / Healthy Volunteers / Molecular Imaging1

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)12.02ChemAxon
pKa (Strongest Basic)3.12ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area67.16 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity74.78 m3·mol-1ChemAxon
Polarizability24.51 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-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-0006-9600000000-952a7c1093fe532d1df3
Mass Spectrum (Electron Ionization)MSsplash10-0006-9500000000-6ab30f52fc69889b3fa2
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0006-9210100010-78b2f412502a142509e6

Taxonomy

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
Monocyclic benzene moiety / Azole / Isoxazole / Heteroaromatic compound / Carboxylic acid hydrazide / Carboxylic acid derivative / Organoheterocyclic compound / Azacycle / Oxacycle / Organooxygen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serotonin binding
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
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. [PubMed:11752352]
  2. Thase ME, Trivedi MH, Rush AJ: MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 1995 May;12(3):185-219. [PubMed:7612154]
  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. [PubMed:2248058]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Primary amine oxidase activity
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
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. [PubMed:4070383]
  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. [PubMed:2248058]

Drug created on June 13, 2005 07:24 / Updated on October 01, 2018 13:01