Isopropyl-α-[2-methylhydrazino]-p-toluamide

Absorption

Procarbazine is rapidly and completely absorbed.

Toxicity

LD50=785 mg/kg (orally in rats)

Chemical properties

Procarbazine is a white to pale yellow crystal- line powder with a slight odor.

The Uses of Isopropyl-α-[2-methylhydrazino]-p-toluamide

antibacterial

The Uses of Isopropyl-α-[2-methylhydrazino]-p-toluamide

Procarbazine was initially synthesized as an MAO inhibitor. However, it was discovered later on that it has ability to act as an alkylating agent and inhibit DNA, RNA, and protein synthesis. Along with this, there is an opinion that procarbazine accumulates in cancerous tissue and generates peroxide and hydroperoxide radicals in cells, which imitates the effect of ionizing radiation. It is used for malignant tumors of lymphatic tissue, brain tumors, lung tumors, and Hodgkin’s disease. A synonym of this drug is natulan.

Indications

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

Background

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

Definition

ChEBI: A benzamide obtained by formal condensation of the carboxy group of 4-[(2-methylhydrazino)methyl]benzoic acid with the amino group of isopropylamine. An antineoplastic chemotherapy drug used for treatment of Hodgkin's lymphoma. Metabolism yields azo-procar azine and hydrogen peroxide, which results in the breaking of DNA strands.

Indications

Procarbazine (Matulane) may autooxidize spontaneously, and during this reaction hydrogen peroxide and hydroxyl free radicals are generated. These highly reactive products may degrade DNA and serve as one mechanism of procarbazine-induced cytotoxicity. Cell toxicity also may be the result of a transmethylation reaction that can occur between the N-methyl group of procarbazine and the N7 position of guanine.

Indications

Procarbazine exhibits an interesting interaction with ethanol, resulting in headaches, diaphoresis, and facial erythema; patients taking this drug should be forewarned to abstain from alcohol. Procarbazine is also a monoamine oxidase (MAO) inhibitor and may potentiate the effects of drugs that are substrates for this enzyme.

brand name

Matulane (Sigma-Tau).

Mechanism of action

Procarbazine is rapidly absorbed after oral administration and has a plasma half-life of only 10 minutes. The drug crosses the blood-brain barrier, reaching levels in CSF equal to those obtained in plasma. Metabolism is extensive and complex. Urinary excretion accounts for 70% of the procarbazine and its metabolites lost during the first 24 hours after drug administration.

Pharmacokinetics

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.

Clinical Use

When originally tested as a single agent in advanced Hodgkin’s disease, procarbazine produced tumor regression responses that were brief, usually lasting only 1 to 3 months. The combination of procarbazine with mechlorethamine, vincristine, and prednisone in the MOPP regimen, however, resulted in an 81% complete remission rate in Hodgkin’s disease. Most of these patients are considered cured. Procarbazine is also used in various combination chemotherapy protocols for non- Hodgkin’s lymphomas and small cell anaplastic (oat cell) carcinoma of the lung. Limited antitumor effects have been observed against multiple myeloma, melanoma, and non–oat cell lung cancers.

Side Effects

The major side effects associated with procarbazine therapy are nausea and vomiting, leukopenia, and thrombocytopenia. Skin rashes have been reported, as have rare cases of allergic interstitial pneumonia. Procarbazine administration produces a high degree of chromosomal breakage, and the compound is mutagenic, teratogenic, and carcinogenic in experimental systems.
Procarbazine may potentiate the effects of tranquilizers and hypnotics. Hypertensive episodes can result if procarbazine is administered simultaneously with adrenomimetic drugs or with tyramine-containing foods. Rarely, a reaction to alcohol similar to that provoked by disulfiram may occur.

Synthesis

Procarbazine, 1-methyl-2-(n-isopropylcarbamoylbenzyl)-hydrazine (30.6.8), is synthesized from 1,2-bis-(benzyloxycarbonyl)-1-methylhydrazine, which is alkylated by the methyl ester of 4-bromomethylbenzoic acid in the presence of sodium hydride, which forms 1,2-bis(benzyloxycarbonyl)-1-methyl-2-(p-carbomethoxy)benzylhydrazine (30.6.6). The carbomethoxy group of this molecule is hydrolyzed by sodium hydroxide, and the resulting carboxyl group is transformed into a acid chloride group, followed by a reaction of this product with isopropylamine gives 1,2-bis-(binzyloxycarbonyl)-1-methyl-2-(p-isopropylcarbamoyl)benzylhydrazine (30.6.7). Hydrolyzis of the benzyloxycarbonyl group in the resulting compound with hydrogen bromide in acetic acid gives the desired procarbazine (30.6.8).

Potential Exposure

Procarbazine is available in capsule form. The primary use of this drug is as an antineoplastic agent in the treatment of advanced Hodgkin’s disease, and oat-cell carcinoma of the lung. The hydrochloride com- pound is used in treatment. The FDA approved use of pro- carbazine hydrochloride in 1969 and indicated that the drug should be used as an adjunct to standard therapy. Possible exposure occurs during manufacture of the drug and direct exposure during its subsequent administration to patients. Some of the metabolites of procarbazine hydrochloride are both carcinostatic and carcinogenic.

Drug interactions

Potentially hazardous interactions with other drugs
Alcohol: may produce a disulfiram reaction.
Antipsychotics: avoid concomitant use with clozapine (increased risk of agranulocytosis).

Carcinogenicity

Procarbazine and procarbazine hydrochloride are reasonably anticipated to be human carcinogens based on sufficient evidence of carcinogenicity from studies in experimental animals. The names “procarbazine” and “procarbazine hydrochloride” are used interchangeably in published studies; because only procarbazine hydrochloride is produced, it has been assumed that procarbazine hydrochloride was the substance under study.

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.

Metabolism

Procarbazine is metabolised to an active alkylating agent by microsomal enzymes in the liver and kidneys and only about 5% is excreted unchanged in the urine. The remainder is oxidised to N-isopropylterephthalamic acid and excreted in the urine, with up to 70% of a dose recovered in the urine after 24 hours.

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides.

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quanti- ties shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.