Procarbazine

Identification

Summary

Procarbazine is an antineoplastic agent indicated for the treatment of stage III and stage IV Hodgkin's disease in combination with other chemotherapeutic agents.

Brand Names
Matulane
Generic Name
Procarbazine
DrugBank Accession Number
DB01168
Background

An antineoplastic agent used primarily in combination with mechlorethamine, vincristine, and prednisone (the MOPP protocol) in the treatment of Hodgkin's disease.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 221.2988
Monoisotopic: 221.152812245
Chemical Formula
C12H19N3O
Synonyms
  • 1-Methyl-2-(p-(isopropylcarbamoyl)benzyl)hydrazine
  • 2-(p-Isopropylcarbamoylbenzyl)-1-methylhydrazine
  • 4-((2-Methylhydrazino)methyl)-N-isopropylbenzamide
  • N-(1-Methylethyl)-4-((2-methylhydrazino)methyl)benzamide
  • N-4-Isopropylcarbamoylbenzyl-N'-methylhydrazine
  • N-isopropyl-4-[(2-methylhydrazino)methyl]benzamide
  • N-Isopropyl-p-(2-methylhydrazinomethyl)-benzamide
  • N-Isopropyl-α-(2-methylhydrazino)-p-toluamide
  • p-(2-Methylhydrazinomethyl)-N-isopropylbenzamide
  • Procarbazin
  • Procarbazina
  • Procarbazine
  • Procarbazinum
External IDs
  • RO-4-6467

Pharmacology

Indication

For use with other anticancer drugs for the treatment of stage III and stage IV Hodgkin's disease.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatNon-hodgkin lymphoma••• •••••
Treatment ofOligodendroglioma••• •••••
Treatment ofPrimary cns lymphoma••• •••••
Used in combination to treatStage 3 hodgkin's diseaseRegimen in combination with: Prednisone (DB00635), Vincristine (DB00541), Mechlorethamine (DB00888)••••••••••••
Used in combination to treatStage 4 hodgkin's diseaseRegimen in combination with: Vincristine (DB00541), Prednisone (DB00635), Mechlorethamine (DB00888)••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Procarbazine is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Procarbazine is cell-phase specific for the S phase of cell division.

Mechanism of action

The precise mode of cytotoxic action of procarbazine has not been clearly defined. There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis. Studies have suggested that procarbazine may inhibit transmethylation of methyl groups of methionine into t-RNA. The absence of functional t-RNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the auto-oxidation of the drug, may attack protein sulfhydryl groups contained in residual protein which is tightly bound to DNA.

TargetActionsOrganism
AMonoamine oxidase
inhibitor
Humans
ADNA
cross-linking/alkylation
Humans
Absorption

Procarbazine is rapidly and completely absorbed.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Procarbazine is metabolized primarily in the liver and kidneys. The drug appears to be auto-oxidized to the azo derivative with the release of hydrogen peroxide. The azo derivative isomerizes to the hydrazone, and following hydrolysis splits into a benzylaldehyde derivative and methylhydrazine. The methylhydrazine is further degraded to CO2 and CH4 and possibly hydrazine, whereas the aldehyde is oxidized to N-isopropylterephthalamic acid, which is excreted in the urine.

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Route of elimination

Not Available

Half-life

10 minutes

Clearance

Not Available

Adverse Effects
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Toxicity

LD50=785 mg/kg (orally in rats)

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 Procarbazine is combined with 1,2-Benzodiazepine.
AbaloparatideProcarbazine may increase the orthostatic hypotensive activities of Abaloparatide.
AbataceptThe risk or severity of adverse effects can be increased when Procarbazine is combined with Abatacept.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Procarbazine is combined with Abciximab.
AcarboseProcarbazine may increase the hypoglycemic activities of Acarbose.
Food Interactions
  • Avoid alcohol. Ingesting alcohol may potentiate the CNS depressant effects of procarbazine and may precipitate a disulfiram-like-reaction (nausea, flushing).
  • Avoid tyramine-containing foods and supplements. Foods that contain tyramine include yogurt, aged cheese, ripe bananas, wine, and sourdough bread.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Procarbazine hydrochlorideXH0NPH5ZX8366-70-1OCSSHHHAHMCFDV-UHFFFAOYSA-N
International/Other Brands
Indicarb / Natulan
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MatulaneCapsule50 mg/1OralLeadiant Biosciences, Inc.1985-12-27Not applicableUS flag
MatulaneCapsule50 mgOralLeadiant Biosciences, Inc1970-12-31Not applicableCanada flag
MatulaneCapsule50 mg/1OralSigma-Tau Pharmaceuticals, Inc.1985-12-272020-03-31US flag

Categories

ATC Codes
L01XB01 — Procarbazine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzamides. These are organic compounds containing a carboxamido substituent attached to a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Benzamides
Alternative Parents
Benzoyl derivatives / Secondary carboxylic acid amides / Alkylhydrazines / Organopnictogen compounds / Organooxygen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Alkylhydrazine / Aromatic homomonocyclic compound / Benzamide / Benzoyl / Carboxamide group / Carboxylic acid derivative / Hydrazine derivative / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
benzamides, hydrazines (CHEBI:71417)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
35S93Y190K
CAS number
671-16-9
InChI Key
CPTBDICYNRMXFX-UHFFFAOYSA-N
InChI
InChI=1S/C12H19N3O/c1-9(2)15-12(16)11-6-4-10(5-7-11)8-14-13-3/h4-7,9,13-14H,8H2,1-3H3,(H,15,16)
IUPAC Name
4-[(2-methylhydrazin-1-yl)methyl]-N-(propan-2-yl)benzamide
SMILES
CNNCC1=CC=C(C=C1)C(=O)NC(C)C

References

Synthesis Reference
US3520926
General References
Not Available
Human Metabolome Database
HMDB0015299
KEGG Drug
D08423
KEGG Compound
C07402
PubChem Compound
4915
PubChem Substance
46507706
ChemSpider
4746
RxNav
8702
ChEBI
71417
ChEMBL
CHEMBL1321
ZINC
ZINC000019166988
Therapeutic Targets Database
DAP000986
PharmGKB
PA451112
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Procarbazine
MSDS
Download (63.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentLymphoma5
3CompletedTreatmentAdvanced Hodgkin Disease1
3CompletedTreatmentBrain and Central Nervous System Tumors4
3CompletedTreatmentBrain Neoplasm / Central Nervous System Neoplasm1
3CompletedTreatmentHodgkin's Lymphoma5

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • AAIPharma Inc.
  • B&B Pharmaceuticals
  • Kaiser Foundation Hospital
  • Sigma-Tau Pharmaceuticals Inc.
Dosage Forms
FormRouteStrength
CapsuleOral50 mg/1
CapsuleOral50 mg
Prices
Unit descriptionCostUnit
Matulane 50 mg capsule55.68USD capsule
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)223 °CNot Available
water solubility1420 mg/LNot Available
logP0.06HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.228 mg/mLALOGPS
logP0.53ALOGPS
logP0.99Chemaxon
logS-3ALOGPS
pKa (Strongest Acidic)15.03Chemaxon
pKa (Strongest Basic)5.56Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area53.16 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity86.98 m3·mol-1Chemaxon
Polarizability25.88 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9954
Blood Brain Barrier+0.9855
Caco-2 permeable+0.6013
P-glycoprotein substrateNon-substrate0.5748
P-glycoprotein inhibitor INon-inhibitor0.8839
P-glycoprotein inhibitor IINon-inhibitor0.9771
Renal organic cation transporterNon-inhibitor0.7974
CYP450 2C9 substrateNon-substrate0.8293
CYP450 2D6 substrateNon-substrate0.702
CYP450 3A4 substrateNon-substrate0.5484
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorInhibitor0.8994
CYP450 3A4 inhibitorNon-inhibitor0.8308
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9414
Ames testNon AMES toxic0.9132
CarcinogenicityCarcinogens 0.6428
BiodegradationNot ready biodegradable0.9741
Rat acute toxicity2.4348 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9785
hERG inhibition (predictor II)Non-inhibitor0.9287
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-MSsplash10-07c6-7920000000-3801345089023dd56325
Mass Spectrum (Electron Ionization)MSsplash10-016u-6900000000-6488b097a4640e8af61a
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0096-0910000000-161c214dc9eb9c75895b
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00ec-0930000000-b24cf0d7216ef4d6040b
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-00di-0090000000-d31452ac03b7855d37fc
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-7920000000-8fc0544155b901473735
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001l-1910000000-8fc876cc1240a5d1dd04
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udl-4900000000-44e3941de4cadfe62d3c
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00l6-6900000000-20d602c6d1829f6bde14
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]-172.1841184
predicted
DarkChem Lite v0.1.0
[M-H]-150.8351
predicted
DeepCCS 1.0 (2019)
[M+H]+172.4027184
predicted
DarkChem Lite v0.1.0
[M+H]+153.23065
predicted
DeepCCS 1.0 (2019)
[M+Na]+171.7307184
predicted
DarkChem Lite v0.1.0
[M+Na]+159.27843
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein group
Organism
Humans
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...

Components:
References
  1. Holt A, Sharman DF, Callingham BA, Kettler R: Characteristics of procarbazine as an inhibitor in-vitro of rat semicarbazide-sensitive amine oxidase. J Pharm Pharmacol. 1992 Jun;44(6):487-93. [Article]
  2. Kraft SL, Baker NM, Carpenter J, Bostwick JR: Procarbazine and antidepressants: a retrospective review of the risk of serotonin toxicity. Psychooncology. 2014 Jan;23(1):108-13. doi: 10.1002/pon.3378. Epub 2013 Aug 29. [Article]
Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Cross-linking/alkylation
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
  3. Ogawa K, Hiraku Y, Oikawa S, Murata M, Sugimura Y, Kawamura J, Kawanishi S: Molecular mechanisms of DNA damage induced by procarbazine in the presence of Cu(II). Mutat Res. 2003 Aug 5;539(1-2):145-55. [Article]
  4. Kyrtopoulos SA, Anderson LM, Chhabra SK, Souliotis VL, Pletsa V, Valavanis C, Georgiadis P: DNA adducts and the mechanism of carcinogenesis and cytotoxicity of methylating agents of environmental and clinical significance. Cancer Detect Prev. 1997;21(5):391-405. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xanthine oxidase activity
Specific Function
Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Ha...
Gene Name
XDH
Uniprot ID
P47989
Uniprot Name
Xanthine dehydrogenase/oxidase
Molecular Weight
146422.99 Da
References
  1. Tweedie DJ, Fernandez D, Spearman ME, Feldhoff RC, Prough RA: Metabolism of azoxy derivatives of procarbazine by aldehyde dehydrogenase and xanthine oxidase. Drug Metab Dispos. 1991 Jul-Aug;19(4):793-803. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48