丙卡巴肼处理（5 和 20 nM；1 小时）显示出不同程度的细胞活力 [1]。

丙卡巴肼（腹腔注射；每天一次；五天；50 和 150 mg/kg）会导致造血细胞中产生微核，但不会增加骨髓 (MF) 中 lacZ 突变的频率 [2]。

细胞活力测定 [1]
细胞类型： L1210 细胞
测试浓度： 5 和 20 nM
孵育时间： 1 小时
实验结果： 5 mM 和 20 mM 时细胞活力分别为 99.3% 和 99.9%。

Animal/Disease Models: Male muta mice (7-8 weeks old) [2]
Doses: 50 and 150 mg/kg
Route of Administration: intraperitoneal (ip) injection; 50 and 150 mg/kg; one time/day; 5-day
Experimental Results: at 50 mg/kg , MN frequency was Dramatically increased, and peripheral blood micronucleus induction was observed.

Absorption, Distribution and Excretion
Procarbazine is rapidly and completely absorbed.
Procarbazine hydrochloride is rapidly and nearly completely absorbed from the GI tract following oral administration. Following oral administration of a single 30 mg dose of radiolabeled procarbazine hydrochloride, peak plasma radioactive concentrations of the drug were attained within 1 hour. Oral administration generally results in plasma concentrations similar to those achieved following IV administration of the drug. /Procarbazine hydrochloride/
Approximately 45% to 70% of a dose is excreted in the urine during the first 24 hr as metabolites.
From 25 to 70% of an oral or parenteral dose given to man is recovered from the urine during the first 24 hours after administration; less than 5% is excreted as the unchanged compound, and the rest is mostly in the form of a metabolite, N-isopropylterephthalanic acid.
Distribution studies in animals and humans using radiolabeled procarbazine hydrochloride administered IV have shown concentrations of radioactivity to be present in the liver, kidneys, intestinal wall and skin. The drug crosses the blood-brain barrier and distributes into CSF. Equilibration of procarbazine between plasma and CSF occurs rapidly following oral administration. It is not known whether procarbazine is distributed into milk.
For more Absorption, Distribution and Excretion (Complete) data for PROCARBAZINE (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
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.
It is rapidly metabolized in man ... . Oxidation of procarbazine produces the corresponding azo compound and hydrogen peroxide. Further metabolism, presumably in the liver, yields azoxy derivatives that circulate in the bloodstream and have potent cytotoxic activity.
Procarbazine yields demethylprocarbazine probably in rats; yields n-isopropyl-alpha-methylazo-p-toluamide and terephthalic isopropylamide in rats. /from table/
Rats biotransformed ip dose of (14)C-monomethylhydrazine to (14)C-methane within 3 min of injection. ... Rats produced 25% (14)C-CH4 and 3% (14)C-CO2 in 90 min. ...(14)C-procarbazine ... was less readily biotransformed to CH4. After 90 min, 4% of dose...excreted as (14)C-CH4. /hydrochloride/
The NADPH-dependent microsomal metabolism of [14C]procarbazine labeled on the terminal N-methyl group resulted in the covalent binding of the drug to exogenously added DNA; this reaction was inhibited by metyrapone. Procarbazine metabolism was also shown to result in covalent binding of the methyl group of the drug to microsomal protein upon metabolism but the extent of protein binding was at least an order of magnitude smaller than that see with its primary oxidative metabolite. N-isopropyl-alpha-(2-methylazo)-p-toluamide. The characteristics of the reactions leading to the covalent binding of the N-methyl group of the azo derivative to microsomal protein and its metabolism to form methane, possessed a number of similarities in the apparent kinetic parameters (Km and Vmax), induction and inhibition patterns indicating a common pathway of metabolism to form a reactive intermediate and the involvement of cytochrome p450. Reduced glutathione stimulated methane formation and inhibited covalent binding to protein.
For more Metabolism/Metabolites (Complete) data for PROCARBAZINE (6 total), please visit the HSDB record page.
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.
Half Life: 10 minutes

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Biological Half-Life
10 minutes
The biological half-life of procarbazine hydrochloride in both plasma and CSF is approximately 1 hour. /Procarbazine hydrochloride/
... Half-life in blood after iv injection is approx 7 min.
The plasma half-life of parent drug is approximately 10 minutes.

Toxicity Summary
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.

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Hepatotoxicity
Mild and transient elevations in serum aminotransferase levels are not uncommon during courses of systemic combination chemotherapy and the role of procarbazine in these abnormalities is often not clear. Aminotransferase elevations arise in more than half of patients and rise above 5 times ULN in 10 to 20% of patients. However, dose modification for serum enzyme elevations is rarely necessary. Clinically apparent liver disease with fever and marked elevations in serum aminotransferase levels without jaundice has been reported but is very rare. A single case report described self-limited, hepatocellular injury without jaundice during a second course of combination therapy and recurrence upon rechallenge with procarbazine, but not with the other antineoplastic agents being used.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Toxicity Data
LD₅₀=785 mg/kg (orally in rats)

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Interactions
Concurrent use /of alcohol/ with procarbazine may result in a disulfiram like reaction and additive central nervous system depression and postural hypotension; also, possible tyramine content in alcoholic beverages, especially beer, wine, or ale, may induce hypertensive reactions.
Concurrent use /of local anesthetics with epinephrine or levonordefrin, or cocaine/ with procarbazine may cause severe hypertension due to sympathomimetic effects. Cocaine should not be administered during or within 14 days following administration of an MAO inhibitor.
Hypotensive effects may be potentiated when spinal anesthetics are used concurrently with procarbazine; discontinuation of procarbazine at least 10 days before elective surgery if spinal anesthesia is planned may be advisable.
Concurrent use /of anticholinergics or other medications with anticholinergic activity, antidyskinetic agents, or antihistamines/ with procarbazine may intensify anticholinergic effects because of the secondary anticholinergic activities of MAO inhibitors; also MAO inhibitors may block detoxification of anticholinergics, thus potentiating their action; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy. Concurrent use with MAO inhibitors may also prolong and intensify CNS depressant and anticholinergic effects of antihistamines; concurrent use is not recommended.
For more Interactions (Complete) data for PROCARBAZINE (22 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat IV 600 mg/kg body weight (at day 59)

[1]. Cytotoxicity and DNA damage caused by the azoxy metabolites of procarbazine in L1210 tumor cells. Cancer Res. 1989 Jan 1;49(1):127-33.

[2]. Procarbazine genotoxicity in the MutaMouse; strong clastogenicity and organ-specific induction of lacZ mutations. Mutat Res. 1999 Aug 18;444(2):269-81.

Therapeutic Uses
Antineoplastic Agents; Carcinogens
MEDICATION (VET): Antineoplastic... /it is used/ exptl, against wide variety of transplanted animal tumors. /hydrochloride/
Procarbazine is indicated, in combination with other agents, for treatment of Hodgkin's disease (Stage III and IV) ... . /Included in US product labeling/
/Procarbazine is indicated, in combination with other agents, for treatment of/ some non-Hodgkin's lymphomas. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for PROCARBAZINE (6 total), please visit the HSDB record page.

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Drug Warnings
Procarbazine is a highly toxic drug and should be used only under constant supervision by a clinician experienced in cancer chemotherapy. When appropriate, procarbazine therapy should be initiated with the patient hospitalized; the patient's clinical and histologic diagnosis and hematologic, renal, and hepatic status should be carefully considered.
Although appropriate studies with procarbazine have not been performed in the geriatric population, the potential for increased vascular accidents (especially in the event of sudden hypertensive episodes), increased sensitivity to hypotensive effects, and reduced metabolic capacity discourages the first-time use of MAO inhibitors in patients over 60 years of age. When an MAo inhibitor is prescribed for an elderly patient, the patient's history of depression, ability to comply with prescribing instructions, and any potential drug interactions must also be considered. In addition, elderly patients are more likely to have age-related renal function impairment, which may require a lower dosage or, in severe cases, avoidance of use of procarbazine.
Patients should be warned not to drink alcoholic beverages and to avoid food with high tyramine content, such as yogurt, cheese, and bananas, while receiving procarbazine. Patients should also be instructed to avoid use of over-the-counter preparations containing antihistamine or sympathomimetic drugs and to discuss any prescription medications they are taking with the clinician who is supervising procarbazine therapy.
Pregnancy risk category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./
For more Drug Warnings (Complete) data for PROCARBAZINE (24 total), please visit the HSDB record page.

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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.

C12H19N3O

221.29876

221.152

671-16-9

Procarbazine Hydrochloride;366-70-1

4915

Typically exists as solid at room temperature

1.0±0.1 g/cm3

384.6±35.0 °C at 760 mmHg

148.9±26.1 °C

0.0±0.9 mmHg at 25°C

1.529

0.77

53.16

3

3

5

16

210

0

O=C(NC(C)C)C1=CC=C(CNNC)C=C1

CPTBDICYNRMXFX-UHFFFAOYSA-N

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)

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。