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Identification
NameIsocarboxazid
Accession NumberDB01247  (APRD00701)
TypeSmall Molecule
GroupsApproved
Description

An MAO inhibitor that is effective in the treatment of major depression, dysthymic disorder, and atypical depression. It also is useful in the treatment of panic disorder and the phobic disorders. (From AMA, Drug Evaluations Annual, 1994, p311)

Structure
Thumb
Synonyms
SynonymLanguageCode
IsocarboxazidaSpanishINN
IsocarboxazideFrenchINN
IsocarboxazidumLatinINN
MarplanNot AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Marplantablet10 mgoralValidus Pharmaceuticals LLC1959-07-01Not AvailableUs
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
EnerzerTakeda
IsocarboxazidAlliance
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number59-63-2
WeightAverage: 231.2505
Monoisotopic: 231.100776675
Chemical FormulaC12H13N3O2
InChI KeyXKFPYPQQHFEXRZ-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylmethylamines. These are compounds containing a phenylmethtylamine moiety, which consists of a phenyl group substituted by an methanamine.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenylmethylamines
Direct ParentPhenylmethylamines
Alternative Parents
Substituents
  • Phenylmethylamine
  • Benzylamine
  • Heteroaromatic compound
  • Oxazole
  • Isoxazole
  • Azole
  • Carboxylic acid hydrazide
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationMay be used to treat major depressive disorder.
PharmacodynamicsIsocarboxazid is a non-selective hydrazine monoamine oxidase (MAO) inhibitor used to treat depression. In vivo and in vitro studies demonstrated inhibition of MAO in the brain, heart, and liver. Depression is a complicated disease that is not fully understood. It is thought that depression may be linked to an imbalance of chemicals within the brain. When depression occurs, there may be a decrease in the amount of chemicals released from nerve cells in the brain. These chemicals are called monoamines. Monoamines are broken down by a chemical called monoamine oxidase. Isocarboxazid prevents monoamine oxidase from breaking down the monoamines. This results in an increased amount of active monoamines in the brain. By increasing the amount of monoamines in the brain, the imbalance of chemicals thought to be caused by depression is altered. This helps relieve the symptoms of depression.
Mechanism of actionIsocarboxazid works by irreversibly blocking the action of a chemical substance known as monoamine oxidase (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). The reduced MAO activity results in an increased concentration of these neurotransmitters in storage sites throughout the central nervous system (CNS) and sympathetic nervous system. This increased availability of one or more monoamines is the basis for the antidepressant activity of MAO inhibitors.
AbsorptionWell absorbed from the gastrointestinal tract.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic and rapid (by oxidation).

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicitySigns of overdose include severe anxiety, confusion, convulsions, cool clammy skin, severe dizziness, severe drowsiness, fast and irregular pulse, fever, hallucinations, severe headache, high or low blood pressure, hyperactive reflexes, muscle stiffness, respiratory depression or failure, slowed reflexes, sweating, severe trouble in sleeping, and unusual irritability.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 substrateNon-inhibitor0.9071
CYP450 2D6 substrateNon-inhibitor0.9231
CYP450 2C19 substrateNon-inhibitor0.9026
CYP450 3A4 substrateNon-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
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Tabletoral10 mg
Prices
Unit descriptionCostUnit
Marplan 10 mg tablet3.45USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point105-106 °CU.S. Patent 2,908,688.
water solubility1.6 mg/mL at 25 °CMEYLAN,WM et al. (1996)
logP1.49HANSCH,C ET AL. (1995)
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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraMS
References
Synthesis Reference

U.S. Patent 2,908,688.

General Reference
  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
External Links
ATC CodesN06AF01
AHFS CodesNot Available
PDB Entries
FDA labelDownload (56.5 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AlmotriptanThe MAO inhibitor, isocarboxazid, may decrease the metabolism and clearance of the serotonin 5-HT receptor agonist, almotriptan. Concomitant therapy is contraindicated.
AltretamineRisk of severe hypotension
AmitriptylinePossibility of severe adverse effects
AmoxapinePossibility of severe adverse effects
AmphetaminePossible hypertensive crisis
AtomoxetinePossible severe adverse reaction with this combination
BenzphetamineMAO Inhibitors may enhance the hypertensive effect of Amphetamines. Concomitant use of amphetamines and monoamine oxidase inhibitors (MAOI) should be avoided. If used concomitantly, careful monitoring of blood pressure must occur. It may take up to 2 weeks after the discontinuation of an MAOI for the effects to dissipate enough to afford safety to the administration of interacting agents.
BezafibrateMAO Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Avoid concomitant use of bezafibrate with monoamine oxidase inhibitors (MAOIs) like isocarboxazid.
BrimonidineMAO Inhibitors like isocarboxazid may enhance the hypertensive effect of Alpha2-Agonists (Ophthalmic). The concomitant use of monoamine oxidase inhibitors and ophthalmic alpha2 agonists is contraindicated.
BuprenorphineBuprenorphine may enhance the adverse/toxic effect of MAO Inhibitors like isocarboxazid. When possible, avoid use of buprenorphine in patients who have used a monoamine oxidase inhibitor within the past 14 days due to possible severe adverse effects.
BupropionPossible severe adverse reaction with this combination
BuspironePossible blood pressure elevation
CitalopramPossible severe adverse reaction with this combination
ClomipraminePossibility of severe adverse effects
DesipraminePossibility of severe adverse effects
DesvenlafaxineIncreased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.
DexfenfluramineRisk of hypertensive crisis.
DextroamphetaminePossible hypertensive crisis
DextromethorphanPossible severe adverse reaction
DiethylpropionPossible hypertensive crisis
DobutamineIncreased arterial pressure
DonepezilPossible antagonism of action
DopamineIncreased arterial pressure
DoxepinPossibility of severe adverse effects
DuloxetinePossible severe adverse reaction with this combination
EntacaponePossible hypertensive crisis with this combination
EphedraIncreased arterial pressure
EphedrineIncreased arterial pressure
EpinephrineIncreased arterial pressure
EscitalopramPossible severe adverse reaction with this combination
FenfluraminePossible hypertensive crisis
FenoterolIncreased arterial pressure
FluoxetinePossible severe adverse reaction with this combination
FluvoxaminePossible severe adverse reaction with this combination
GalantaminePossible antagonism of action
GuanethidineIsocarboxazid may decrease the effect of guanethidine.
ImipraminePossibility of severe adverse effects
IsoprenalineIncreased arterial pressure
L-DOPAPossible hypertensive crisis
L-TryptophanPossible severe adverse reaction with this combination
MazindolPossible hypertensive crisis
MephentermineIncreased arterial pressure
MetaraminolIncreased arterial pressure
MethamphetaminePossible hypertensive crisis
MethotrimeprazinePossible severe adverse reaction with this combination
MethoxamineIncreased arterial pressure
MethylphenidatePossible hypertensive crisis with this combination
MidodrinePossible hypertensive crisis with this combination
MilnacipranIncrease serotonin levels. Combination therapy is contraindicated.
MirtazapinePossible severe adverse reaction with this combination
NaratriptanThe use of two serotonin modulators increases the risk of serotonin syndrome. Consider alternate therapy or monitor for signs and symptoms of serotonin syndrome.
NefazodonePossible severe adverse reaction with this combination
NorepinephrineIncreased arterial pressure
NortriptylinePossibility of severe adverse effects
OrciprenalineIncreased arterial pressure
ParoxetinePossible severe adverse reaction with this combination
PethidinePotentially fatal adverse effects
PhendimetrazinePossible hypertensive crisis
PhenmetrazinePossible hypertensive crisis
PhenterminePossible hypertensive crisis
PhenylephrineIncreased arterial pressure
PhenylpropanolamineIncreased arterial pressure
PirbuterolIncreased arterial pressure
ProcaterolIncreased arterial pressure
ProtriptylinePossibility of severe adverse effects
PseudoephedrineIncreased arterial pressure
RivastigminePossible antagonism of action
RizatriptanThe MAO inhibitor, isocarboxazid, may decrease the metabolism and clearance of the serotonin 5-HT receptor agonist, rizatriptan. Concomitant therapy is contraindicated.
SalbutamolIncreased arterial pressure
SertralinePossible severe adverse reaction with this combination
SibutraminePossible serotoninergic syndrome with this combination
SumatriptanThe MAO inhibitor, isocarboxazid, may decrease the metabolism and clearance of the serotonin 5-HT receptor agonist, sumatriptan. Concomitant therapy is contraindicated.
TacrineThe therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Isocarboxazid, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.
TerbutalineIncreased arterial pressure
TetrabenazineTetrabenazine may increase the adverse/toxic effects of Isocarboxazid. Concomitant therapy is contraindicated.
TolcaponeTolcapone and Isocarboxazid decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
TramadolTramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, isocarboxazid.
TranylcypromineIncreased risk of serotonin syndrome. Use caution during concomitant therapy and monitor for symptoms of serotonin syndrome.
TrazodoneIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
TrimethobenzamideTrimethobenzamide and Isocarboxazid, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
TrimipramineIncreased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Avoid combination or monitor for symptoms of serotonin syndrome and/or hypertensive crisis.
TriprolidineTriprolidine and Isocarboxazid, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.
TrospiumTrospium and Isocarboxazid, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.
VenlafaxineIncreased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.
VilazodoneMAO Inhibitors may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Avoid combination.
ZolmitriptanThe MAO inhibitor, isocarboxazid, may increase the serum concentration of zolmitriptan by decreasing its metabolism. Concomitant therapy and use of zolmitriptan within two weeks of discontinuing isocarboxazid are contraindicated.
Food Interactions
  • Take without regard to meals, avoid tyramine, caffeine and alcohol.

Targets

1. Amine oxidase [flavin-containing] A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Amine oxidase [flavin-containing] A P21397 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Thase ME, Trivedi MH, Rush AJ: MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 1995 May;12(3):185-219. Pubmed
  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

2. Amine oxidase [flavin-containing] B

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Amine oxidase [flavin-containing] B P27338 Details

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
  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

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Drug created on June 13, 2005 07:24 / Updated on May 02, 2014 14:23