Identification

Name
Procarbazine
Accession Number
DB01168  (APRD00695)
Type
Small Molecule
Groups
Approved, Investigational
Description

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

Structure
Thumb
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
  • Procarbazinum
External IDs
RO-4-6467
Product Ingredients
IngredientUNIICASInChI Key
Procarbazine hydrochlorideXH0NPH5ZX8366-70-1OCSSHHHAHMCFDV-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MatulaneCapsule50 mgOralLeadiant Biosciences, Inc1970-12-31Not applicableCanada
MatulaneCapsule50 mg/1OralLeadiant Biosciences, Inc.1985-12-27Not applicableUs
MatulaneCapsule50 mg/1OralSigma Tau Pharmaceuticals, Inc.1985-12-27Not applicableUs
International/Other Brands
Indicarb / Natulan
Categories
UNII
35S93Y190K
CAS number
671-16-9
Weight
Average: 221.2988
Monoisotopic: 221.152812245
Chemical Formula
C12H19N3O
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

Pharmacology

Indication

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

Associated Conditions
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
ADNA
cross-linking/alkylation
Human
AMonoamine oxidase
inhibitor
Human
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.

Route of elimination
Not Available
Half life

10 minutes

Clearance
Not Available
Toxicity

LD50=785 mg/kg (orally in rats)

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of adverse effects can be increased when Procarbazine is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of adverse effects can be increased when Procarbazine is combined with (S)-Warfarin.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Procarbazine is combined with 2-Methoxyethanol.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when Procarbazine is combined with 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of serotonin syndrome can be increased when Procarbazine is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of serotonin syndrome can be increased when Procarbazine is combined with 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of serotonin syndrome can be increased when Procarbazine is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe risk or severity of adverse effects can be increased when Procarbazine is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Procarbazine is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of serotonin syndrome can be increased when Procarbazine is combined with 5-methoxy-N,N-dimethyltryptamine.
Food Interactions
Not Available

References

Synthesis Reference
US3520926
General References
Not Available
External Links
Human Metabolome Database
HMDB0015299
KEGG Drug
D08423
KEGG Compound
C07402
PubChem Compound
4915
PubChem Substance
46507706
ChemSpider
4746
ChEBI
71417
ChEMBL
CHEMBL1321
Therapeutic Targets Database
DAP000986
PharmGKB
PA451112
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Procarbazine
ATC Codes
L01XB01 — Procarbazine
MSDS
Download (63.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0WithdrawnTreatmentBrain and Central Nervous System Tumors / Malignant Lymphomas / Neurologic toxicity1
1CompletedTreatmentBone Marrow Suppression / Brain and Central Nervous System Tumors / Drug/Agent Toxicity by Tissue/Organ1
1, 2Active Not RecruitingTreatmentLymphoma, Hodgkins1
1, 2CompletedTreatmentBrain and Central Nervous System Tumors1
2Active Not RecruitingTreatmentChemotherapeutic Agent Toxicity / Cognitive/Functional Effects / Malignant Lymphomas / Neurologic toxicity / Radiation Toxicity1
2Active Not RecruitingTreatmentLymphoma, Hodgkins1
2Active Not RecruitingTreatmentMalignant Lymphomas1
2Active Not RecruitingTreatmentMalignant Lymphomas / Nonneoplastic Condition1
2CompletedTreatmentBrain and Central Nervous System Tumors4
2CompletedTreatmentHodgkins Disease (HD) / Pediatric1
2CompletedTreatmentLymphoma, Hodgkins1
2CompletedTreatmentMalignant Lymphomas7
2CompletedTreatmentMalignant Lymphomas / Neurologic toxicity1
2CompletedTreatmentNon-Hodgkin's Lymphoma (NHL)1
2Not Yet RecruitingTreatmentPrimary Central Nervous System Lymphoma (PCNSL)1
2RecruitingTreatmentAIDS-Related Diffuse Large Cell Lymphoma / AIDS-Related Diffuse Mixed Cell Lymphoma / AIDS-Related Diffuse Small Cleaved Cell Lymphoma / AIDS-related Immunoblastic Large Cell Lymphoma / AIDS-Related Lymphoblastic Lymphoma / AIDS-related Peripheral/Systemic Lymphoma / AIDS-related Small Noncleaved Cell Lymphoma / Stage III AIDS-related Lymphoma / Stage IV AIDS-related Lymphoma1
2RecruitingTreatmentLymphoma, Hodgkins1
2SuspendedTreatmentMalignant Lymphomas1
2TerminatedTreatmentMalignant Lymphomas1
2Unknown StatusTreatmentHIV-associated Hodgkin Lymphoma1
2Unknown StatusTreatmentMalignant Lymphomas1
2Unknown StatusTreatmentNewly Diagnosed Non Methylated Glioblastoma Multiforme Grade 41
2Unknown StatusTreatmentPrimary Non Hodgkin Lymphoma of the Central Nervous System1
2Unknown StatusTreatmentRecurrent Glioblastoma Multiforme1
2WithdrawnTreatmentMalignant Lymphomas1
2, 3CompletedTreatmentBrain and Central Nervous System Tumors1
3Active Not RecruitingTreatmentLymphoma, Hodgkins1
3Active Not RecruitingTreatmentMalignant Lymphomas5
3CompletedTreatmentBrain and Central Nervous System Tumors4
3CompletedTreatmentLymphoma, Hodgkins3
3CompletedTreatmentMalignant Lymphomas2
3CompletedTreatmentNeoplasms, Brain / Tumors, Central Nervous System1
3RecruitingTreatmentBrain and Central Nervous System Tumors1
3RecruitingTreatmentClassical Hodgkin Lymphoma1
3Unknown StatusTreatmentBrain and Central Nervous System Tumors1
3WithdrawnTreatmentBrain and Central Nervous System Tumors1
Not AvailableActive Not RecruitingTreatmentAdvanced Hodgkin's Lymphoma1
Not AvailableCompletedTreatmentAtaxia-Telangiectasia1
Not AvailableCompletedTreatmentMalignant Lymphomas1
Not AvailableNot Yet RecruitingTreatmentRecurrent High-grade Glioma1
Not AvailableUnknown StatusTreatmentMalignant Lymphomas2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • AAIPharma Inc.
  • B&B Pharmaceuticals
  • Kaiser Foundation Hospital
  • Sigma-Tau Pharmaceuticals Inc.
Dosage forms
FormRouteStrength
CapsuleOral50 mg
CapsuleOral50 mg/1
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)5.6ChemAxon
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-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-016u-6900000000-6488b097a4640e8af61a
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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0096-0910000000-161c214dc9eb9c75895b

Taxonomy

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
Benzamide / Benzoyl / Secondary carboxylic acid amide / Carboxamide group / Alkylhydrazine / Carboxylic acid derivative / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound / Organic oxide
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
benzamides, hydrazines (CHEBI:71417)

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Yes
Actions
Cross-linking/alkylation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
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. [PubMed:17139284]
  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. [PubMed:17016423]
  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. [PubMed:12948823]
  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. [PubMed:9307842]
Kind
Protein group
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...

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. [PubMed:1359073]
  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. [PubMed:24038727]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1B1
Uniprot ID
Q16678
Uniprot Name
Cytochrome P450 1B1
Molecular Weight
60845.33 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 08:41