Procarbazine significantly reduces the weight of the testicles and epididyma, as well as haploid cells and spermatogenic arrest. These effects show variation in the test golden hamster population.[3] In brown adipose tissue, procarbazine causes a dose-dependent potentiation of MAO A. The elevation is more noticeable after monomethylhydrazine, with activity in rat homogenates reaching 350% of that in control homogenates. This amine's metabolism is decreased by procarbazine or monomethylhydrazine to an extent that is comparable to what was found ex vivo in blood vessel homogenates.[4] Procarbazine is a broad-spectrum carcinogen in rodents and monkeys, resulting in tumors of the nervous system, lung, mammary gland, and hematopoietic system. It is also mutagenic, clastogenic, and teratogenic in a variety of test systems of differing complexity. Under complex metabolic conditions, procarbazine in vivo produces a variety of chemically reactive species, such as free radicals and methylating agents.[5]

Cell Line: L1210 cells
Concentration: 5 and 20 nM
Incubation Time: 1 hour
Result: Showed 99.3% and 99.9% survival of cells at 5 mM and 20 mM, respectively.

Male muta mouse (7–8 weeks old)
50 and 150 mg/kg
Intraperitoneal injection; 50 and 150 mg/kg; once daily; 5 days

Absorption, Distribution and Excretion
Procarbazine is rapidly and completely absorbed. After oral administration, procarbazine hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma drug concentration is reached within 1 hour after a single oral dose of 30 mg of radiolabeled procarbazine hydrochloride. Oral administration typically achieves similar plasma concentrations to intravenous administration. /Procarbazine Hydrochloride/ Approximately 45% to 70% of the dose is excreted in the urine as metabolites within 24 hours after administration. Of the oral or parenteral dose administered to humans, 25% to 70% is recovered in the urine within 24 hours after administration; less than 5% is excreted unchanged, with the remainder mostly excreted as the metabolite N-isopropylterephthalic acid. Distribution studies in animals and humans have shown that radioactive material is present in the liver, kidneys, intestinal wall, and skin after intravenous injection of radiolabeled procarbazine hydrochloride. The drug can cross the blood-brain barrier and distribute into the cerebrospinal fluid. Following oral administration, procarbazine rapidly reaches equilibrium between plasma and cerebrospinal fluid. It is currently unclear whether procarbazine is distributed into breast milk.
For more complete data on absorption, distribution, and excretion of procarbazine (6 items), please visit the HSDB record page.

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Metabolism/Metabolites
Procarbazine is primarily metabolized in the liver and kidneys. The drug appears to undergo auto-oxidation, generating an azo derivative and releasing hydrogen peroxide. The azo derivative is isomerized to a hydrazone, which is hydrolyzed and cleaved into a benzaldehyde derivative and methylhydrazine. The methylhydrazine is further degraded to carbon dioxide and methane, possibly also generating hydrazine, while the aldehyde is oxidized to N-isopropylterephthalic acid, which is excreted in the urine.
It is rapidly metabolized in the human body… Oxidation of procarbazine produces the corresponding azo compound and hydrogen peroxide. Further metabolism (possibly in the liver) produces azo oxide derivatives, which circulate in the blood and possess potent cytotoxic activity.
Procarbazine may be converted into demethylprocarbazine in rats; N-isopropyl-α-methylazo-p-toluamide and isopropylamide terephthalate are also generated in rats. /Excerpt from Table/
Intraperitoneal injection of (14)C-monomethyl hydrazine in rats results in its bioconversion to (14)C-methane within 3 minutes. ...Rats produce 25% (14)C-CH4 and 3% (14)C-CO2 within 90 minutes. ...(14)C-procarbazine ... has a low bioconversion efficiency to CH4. After 90 minutes, 4% of the dose ... is excreted as (14)C-CH4. /Hydrochloride/
NADPH-dependent microsomal metabolism of terminally N-methyl-tagged [14C]procarbazine leads to covalent binding of the drug to exogenously added DNA; this reaction can be inhibited by metheprone. The metabolism of procarbazine also revealed that the methyl group of the drug covalently binds to microsomal proteins during metabolism, but this protein binding is at least an order of magnitude less than that of its major oxidative metabolite, N-isopropyl-α-(2-methylazo)-p-toluamide. The covalent binding of the N-methyl group of the azo derivative to microsomal proteins and its methane-producing reaction characteristics share many similarities in apparent kinetic parameters (Km and Vmax), induction and inhibition patterns, suggesting a common metabolic pathway, the generation of active intermediates, and the involvement of cytochrome P450. Reduced glutathione promotes methane formation and inhibits covalent binding to proteins. For more complete metabolic/metabolite data on procarbazine (6 metabolites), please visit the HSDB record page. Procarbazine is primarily metabolized in the liver and kidneys. The drug appears to undergo auto-oxidation, generating azo derivatives and releasing hydrogen peroxide. The azo derivatives are isomerized to hydrazones, which hydrolyze to benzaldehyde derivatives and methylhydrazine. Methylhydrazine further degrades into carbon dioxide and methane, possibly also producing hydrazine, while the aldehyde is oxidized to N-isopropylterephthalic acid, which is excreted in the urine.
Half-life: 10 minutes

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Biological half-life
10 minutes
The biological half-life of procarbazine hydrochloride in plasma and cerebrospinal fluid is approximately 1 hour. /Procarbazine hydrochloride/
…The half-life in blood after intravenous injection is approximately 7 minutes.
The plasma half-life of the parent drug is approximately 10 minutes.

Toxicity Summary
The exact mechanism of cytotoxicity of procarbazine is not fully understood. Evidence suggests that the drug may act by inhibiting the synthesis of proteins, RNA, and DNA. Studies have shown that procarbazine may inhibit the process of methionine methyl transfer to tRNA. Loss of functional tRNA may lead to the cessation of protein synthesis, which in turn leads to the cessation of DNA and RNA synthesis. Furthermore, procarbazine may directly damage DNA. Hydrogen peroxide produced during drug autoxidation may attack sulfhydryl groups in residual proteins that are tightly bound to DNA. Hepatotoxicity
Mild and transient elevations in serum transaminase levels are not uncommon during systemic combination chemotherapy, and the role of procarbazine in these abnormalities is generally unclear. More than half of patients experience elevated transaminase levels, with 10% to 20% experiencing levels exceeding five times the upper limit of normal. However, dose adjustments are rarely necessary due to elevated serum enzymes. While clinically significant liver disease with fever and significantly elevated serum transaminase levels has been reported, this is extremely rare. One case report described self-limiting hepatocellular injury without jaundice during a second cycle of combination therapy, which relapsed after re-administration of procarbazine but did not relapse with other antitumor drugs. Probability score: D (likely a rare cause of clinically significant liver injury). Toxicity data: LD50 = 785 mg/kg (oral in rats). Interactions: Concomitant use of procarbazine with alcohol may cause a disulfiram-like reaction and exacerbate central nervous system depression and orthostatic hypotension; furthermore, alcoholic beverages (especially beer, wine, or malt spirits) may contain tyramine, which may lead to a hypertensive response. Concomitant use of local anesthetics (such as epinephrine or levonorepinephrine) or cocaine with procarbazine may cause severe hypertension due to sympathomimetic effects. Cocaine should not be used during or within 14 days after taking monoamine oxidase inhibitors.
The hypotensive effect may be enhanced when using spinal anesthetics and procarbazine concurrently; if spinal anesthesia is planned, it is recommended to discontinue procarbazine at least 10 days before elective surgery.
Concurrent use of anticholinergic drugs or other drugs with anticholinergic activity, antimotor dyskinesia drugs, or antihistamines with procarbazine may enhance the anticholinergic effect due to the secondary anticholinergic activity of monoamine oxidase inhibitors. Furthermore, monoamine oxidase inhibitors (MAO inhibitors) may block the detoxification effect of anticholinergic drugs, thereby enhancing their effect; patients should be advised to report gastrointestinal problems promptly, as concurrent use of MAO inhibitors may lead to paralytic ileus. Concurrent use with MAO inhibitors may also prolong and enhance the central nervous system depressant and anticholinergic effects of antihistamines; concurrent use is not recommended.
For more complete interaction data on procarbazine (22 in total), please visit the HSDB record page.

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Non-human toxicity values
Rat intravenous injection LD50: 600 mg/kg body weight (day 59)

[1]. Mutat Res . 2003 Aug 5;539(1-2):145-55.

[2]. Mutat Res . 1999 Aug 18;444(2):269-81.

[3]. Arch Androl . 2002 Mar-Apr;48(2):91-100.

[4]. J Pharm Pharmacol . 1995 Oct;47(10):837-45.

[5]. Carcinogenesis . 1997 Nov;18(11):2191-6.

Therapeutic Uses

Antitumor drug; carcinogen
Veterinary drug: Antitumor drug…/For/experimental treatment of various transplanted animal tumors. /Hydrochloride/
Procarbazine, in combination with other drugs, is indicated for the treatment of Hodgkin lymphoma (stages III and IV)…/Included in the US product label/
/Procarbazine, in combination with other drugs, is indicated for the treatment of/certain non-Hodgkin lymphomas. /Not included in the US product label/
For more complete therapeutic use data for procarbazine (6 types in total), please visit the HSDB record page.

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Drug Warnings
Procarbazine is a highly toxic drug and should only be used under the continuous supervision of an experienced cancer chemotherapy clinician. If applicable, procarbazine treatment should be initiated during the patient's hospitalization; the patient's clinical and histological diagnosis, as well as hematological, renal, and hepatic conditions, should be carefully evaluated. Although studies on procarbazine in the elderly have not been conducted, given the increased risk of vascular events (especially in cases of sudden hypertension), increased sensitivity to antihypertensive effects, and decreased metabolic capacity in older patients, the use of monoamine oxidase inhibitors (MAOIs) for the first time is not recommended for patients over 60 years of age. When prescribing MAOIs to older patients, their history of depression, adherence to medication, and any potential drug interactions must also be considered. Furthermore, older patients are more prone to age-related renal impairment, which may necessitate dose reduction, or in severe cases, avoidance of procarbazine. Patients taking procarbazine should be advised to abstain from alcohol and avoid foods high in tyramine, such as yogurt, cheese, and bananas. Patients should also be advised to avoid over-the-counter medications containing antihistamines or sympathomimetic drugs and to discuss any prescription medications they are taking with their clinician treating their procarbazine treatment. Pregnancy Risk Grade: D/Positive evidence of risk exists. Human studies, trial data, and post-marketing data have confirmed fetal risk. However, the potential benefits of using this drug may outweigh the potential risks. For example, this drug may be suitable in life-threatening situations or when a patient has a serious illness and other safer medications are unavailable or ineffective. For more complete data on drug warnings for procarbazine (24 in total), please visit the HSDB records page.

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Pharmacodynamics
Procarbazine is an alkylating agent used to treat a variety of cancers. Alkylating agents are named for their ability to add alkyl groups to numerous electronegative groups under specific intracellular conditions. They inhibit tumor growth by cross-linking guanine bases in the DNA double helix—directly attacking the DNA. This prevents the DNA strands from unwinding and separating. Since DNA replication requires unwinding and separation, cells cannot divide. Furthermore, these drugs can add methyl or other alkyl groups to molecules that shouldn't be present, inhibiting the proper use of base pairing and leading to DNA mismatches. Procarbazine is a cell-phase specific drug for the S phase of cell division.

C12H19N3O.HCL

257.76

257.129

C, 55.92; H, 7.82; Cl, 13.75; N, 16.30; O, 6.21

366-70-1

671-16-9

4915

White to off-white solid powder

384.6ºC at 760 mmHg

223ºC

148.9ºC

3.023

3

3

5

16

210

0

O=C(C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])N([H])N([H])C([H])([H])[H])N([H])C([H])(C([H])([H])[H])C([H])([H])[H]

DERJYEZSLHIUKF-UHFFFAOYSA-N

InChI=1S/C12H19N3O.ClH/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);1H

4-[(2-methylhydrazinyl)methyl]-N-propan-2-ylbenzamide;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (8.07 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.67 mg/mL (6.48 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.67 mg/mL (6.48 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (387.96 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)