Absorption, Distribution and Excretion
Male Sprague-Dawley rats received a single intraperitoneal injection (45 mg/kg) of radiolabeled 1-methyl-2-pyrrolidone. Plasma concentrations of radioactivity and the compound were monitored for 6 hours, revealing a rapid distribution phase followed by a slow elimination phase. The majority of the labeled substance was excreted in the urine within 12 hours, approximately 75% of the labeled dose. … This study evaluated the toxicokinetics of N-((14)C)methylpyrrolidone (((14)C)NMP) in hairy male Sprague-Dawley rats following intravenous injection (0.1, 1, 10, 100, and 500 mg/kg, dissolved in saline) or topical application (20 and 40 μL/cm²; 10 cm², undiluted). Regardless of the dose, unmetabolized NMP rapidly distributed throughout the body, reaching a volume of distribution of 69% of body weight. Following this phase, unmetabolized NMP decreased almost linearly over 3 to 4 hours post-dose, followed by a single exponential decrease in the three lowest-dose groups (half-life t1/2 = 0.8 hours). Peak plasma concentrations of the major metabolite, 5-hydroxy-N-methylpyrrolidone (5-HNMP), were reached 4 to 6 hours post-dose in the three lowest-dose groups, and 8 to 24 hours post-dose in the highest-dose group. These results indicate that NMP elimination is controlled by saturated metabolic processes. The Michaelis constant estimated from the plasma concentration of unmetabolized NMP was 2 mM and 3.8 mg/h, respectively. 4% to 10% of the administered dose was excreted in the urine as unmetabolized NMP. The urinary clearance of NMP (0.03 to 0.07 mL/min) indicates strong renal tubular reabsorption. 5-HNMP was the major urinary metabolite, accounting for 42% to 55% of the administered dose. Peak urinary excretion occurred 4 to 6 hours post-administration (lowest three dose groups) and 8 to 24 hours (highest two dose groups). Urinary clearance (0.9 to 1.3 mL/min) was consistent with simple glomerular filtration clearance. Metabolic studies were conducted in rats using N-methyl-2-pyrrolidone labeled with 14C and tritium. Male Sprague-Dawley rats were injected with labeled or unlabeled N-methyl-2-pyrrolidone at a dose of 45 mg/kg body weight. Urine, feces, exhaled breath, and bile were collected at various time points from administration to sacrifice. In pharmacokinetic studies, serial blood samples were collected and analyzed between 30 minutes and 6 hours post-injection. High-performance liquid chromatography (HPLC) analysis of N-methyl-2-pyridinone in plasma showed a rapid distribution phase followed by a slow elimination phase; the half-life of the 14C-labeled N-methyl-2-pyridinone was approximately 7 hours, and that of the tritium-labeled N-methyl-2-pyridinone was approximately 10 hours. Within 12 hours, approximately 70% of the total dose was excreted in urine, maintaining a drug-to-dose ratio of 2:1 in urine. The tissue distribution patterns of the radiolabeled isomers were similar. The tissue accumulation concentrations, from highest to lowest, were: liver, intestine, testes, stomach, kidneys, lungs, brain, heart, pancreas, and spleen. The concentrations of N-methyl-2-pyrrolidone in the bladder, thyroid, and thymus were extremely low. Six male volunteers were exposed to 0, 10, 25, and 50 mg/m³ of N-methyl-2-pyrrolidone over four days, with each exposure lasting eight hours. …N-methyl-2-pyrrolidone is absorbed via the respiratory tract and is readily excreted from the body, primarily through biotransformation into other compounds. …For more complete data on the absorption, distribution, and excretion of 1-methyl-2-pyrrolidone (a total of 8), please visit the HSDB records page.

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Metabolism/Metabolites
This study aimed to investigate the metabolic pathway of N-methyl-2-pyrrolidone in humans. Three healthy male volunteers received an oral dose of 100 mg of N-methyl-2-pyrrolidone. All urine samples were collected over nine consecutive days. Metabolites were identified and quantified using gas chromatography/mass spectrometry (GC/MS). N-methyl-2-pyrrolidone, 5-hydroxy-N-methyl-2-pyrrolidone (5-hydroxy-N-methyl-2-pyrrolidone), N-methylsuccinimide, and 2-hydroxy-N-methylsuccinimide were detected in urine. The mean excretion fractions of N-methyl-2-pyrrolidone, 5-hydroxy-N-methyl-2-pyrrolidone, N-methylsuccinimide, and 2-hydroxy-N-methylsuccinimide were 0.8%, 44%, 0.4%, and 20%, respectively.
N-methyl-2-pyrrolidone, 5-hydroxy-N-methyl-2-pyrrolidone, or 2-hydroxy-N-methylsuccinimide were not detected bound to glucuronic acid or sulfate. One-third of orally administered N-methyl-2-pyrrolidone was not recovered in urine as N-methyl-2-pyrrolidone, 5-hydroxy-N-methyl-2-pyrrolidone, N-methylsuccinimide, or 2-hydroxy-N-methylsuccinimide. The half-lives of 5-hydroxy-N-methyl-2-pyrrolidone, N-methylsuccinimide, and 2-hydroxy-N-methylsuccinimide in urine are approximately 4 hours, 8 hours, and 17 hours, respectively. This paper establishes a method for determining N-methylsuccinimide and 2-hydroxy-N-methylsuccinimide in human urine and N-methylsuccinimide in human plasma. N-Methylsuccinimide and 2-hydroxy-N-methylsuccinimide are metabolites of the organic solvent N-methyl-2-pyrrolidone. This method is applicable to the analysis of urine and plasma samples from workers exposed to N-methyl-2-pyrrolidone. This study describes the procedure for isolating and identifying the major urinary metabolites of N-methylpyrrolidone after intravenous injection in male Sprague-Dawley rats. Rats were injected via tail vein with unlabeled or 14C-labeled N-methylpyrrolidone at a dose of 45 mg/kg. Urine was collected at 0–12 h, 12–24 h, and 24–48 h post-administration and analyzed using gas chromatography/mass spectrometry (GC/MS). Samples purified by high-performance liquid chromatography (HPLC) were then analyzed by thermal spray HPLC/MS. Based on thin-layer chromatography and mass spectrometry analysis and comparison with standard samples, the major metabolite was associated with 5-hydroxy-N-methylpyrrolidone.
1-Methyl-2-pyrrolidone is rapidly biotransformed into 5-hydroxy-N-methyl-2-pyrrolidone via hydroxylation, which is further oxidized to N-methylsuccinimide; this intermediate is further hydroxylated to 2-hydroxy-N-methylsuccinimide. These metabolites are all colorless. Following inhalation or oral administration, the excretion of NMP metabolites in the urine is approximately 100% and 65% of the administered dose, respectively.

Toxicity Data
LCLo (Rat) = 1,000 mg/m³ Interactions This study investigated the ability of N-methylpyrrolidone and polar lipids to enhance the transdermal delivery of metronidazole in vitro using full-thickness human non-occlusive skin. Fatty acids and ethanol were also tested, revealing that they both enhanced metronidazole penetration in a propylene glycol carrier; N-methylpyrrolidone enhanced metronidazole penetration in an isopropyl myristate carrier, but had no effect on the propylene glycol carrier. N-methylpyrrolidone, alone or in combination with isopropyl myristate, rapidly penetrated the skin. These results indicate that changes in skin barrier permeability to metronidazole are correlated with the skin penetration rate of N-methylpyrrolidone. This study also investigated the effects of the penetration enhancers N-methylpyrrolidone (N-methyl-2-pyrrolidone) or isopropyl myristate on the in vitro permeability of gonadotropin-releasing hormone (LHRH) through porcine epidermis. Compared with the control group, the permeability coefficient of the epidermis treated with the permeability enhancer was significantly increased. The study concluded that both permeability enhancers can enhance the transdermal absorption of peptide drugs such as gonadotropin-releasing hormone (GnRH). This study investigated the effects of lauroylcapram (Azone; 1-dodecylazacycloheptan-2-one; I), N-methylpyrrolidone (N-methyl-2-pyrrolidone; II), and dodecyl-L-pyroglutamate (III) on the transdermal absorption of insulin (IV) and FD&C Blue 1 (Brilliant Blue FCF; V) in an in vitro permeation chamber; these compounds were formulated into 40% propylene glycol solutions with increasing concentrations. …In the presence of II, the permeability of V was improved, and II concentrations from 6.0% to 20.0% showed the same effect. In the experiment with IV, the optimal concentration of II was found to be close to 10.0%, and excessively high or low concentrations led to decreased efficacy. ...

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Non-human toxicity values
Oral LD50 in rats: 3914 mg/kg
Oral LD50 in rats: 4.2 ml/kg
Oral LD50 in mice: 7725 mg/kg
Dermal LD50 in rabbits: 8000 mg/kg
For more complete data on non-human toxicity values for 1-methyl-2-pyrrolidone (out of 13), please visit the HSDB record page.

[1]. Nitrate stimulation of N-Methylpyrrolidone biodegradation by Paracoccus pantotrophus: Metabolite mechanism and Genomic characterization. Bioresour Technol. 2019 Dec;294:122185.

[2]. Novel Metabolic Pathway for N-Methylpyrrolidone Degradation in Alicycliphilus sp. Strain BQ1. Appl Environ Microbiol. 2017 Dec 15;84(1):e02136-17.

According to the U.S. Environmental Protection Agency (EPA), N-methylpyrrolidone may have developmental toxicity. N-Methyl-2-pyrrolidone is a clear, colorless liquid with a fishy odor. It is denser than water. Its flash point is 199°F (90°C). Contact may irritate skin, eyes, and mucous membranes. Ingestion may cause poisoning. N-Methylpyrrolidone belongs to the pyrrolidone class of compounds, in which the hydrogen atom bonded to the nitrogen atom is replaced by a methyl group. It is a polar aprotic solvent. It is an N-alkylpyrrolidine, belonging to the lactam class of compounds, and also a pyrrolidone-2-one class. N-Methylpyrrolidone is being investigated for the treatment of multiple myeloma. 1-Methyl-2-pyrrolidone has been reported to exist in Microtropis japonica, Melicope hayesii, and other organisms with relevant data.
1-Methyl-2-pyrrolidone, or N-methyl-2-pyrrolidone (NMP), is a compound with a five-membered lactam structure. It is a colorless to slightly yellow liquid that is miscible with water. It is used in petrochemical processing and can also be used as a solvent or paint remover for the surface treatment of textiles, resins and metal-coated plastics. In the pharmaceutical industry, N-methyl-2-pyrrolidone is used in the formulation of oral and transdermal drugs. NMP has been identified as a reproductive toxicant, first by the state of California in 2001[3] and by the European Commission in 2003. Faced with increasingly stringent regulations, some manufacturers are considering using alternative solvents in certain applications, especially in situations where worker exposure is difficult to control, such as paint stripping, graffiti removal and agriculture. (Wikipedia)

C5H9NO

99.13

99.068

872-50-4

N-Methyl-2-pyrrolidone-d3;933-86-8

13387

Colorless to light yellow liquid

1.0±0.1 g/cm3

202.0±0.0 °C at 760 mmHg

−24 °C(lit.)

86.1±0.0 °C

0.3±0.4 mmHg at 25°C

1.470

-0.4

0

1

0

7

90.1

0

O=C1CCCN1C

SECXISVLQFMRJM-UHFFFAOYSA-N

InChI=1S/C5H9NO/c1-6-4-2-3-5(6)7/h2-4H2,1H3

1-methylpyrrolidin-2-one

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)

DMSO: 100 mg/mL (1008.78 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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