Toxicokinetics and Metabolism of<i>N-</i>[<sup>14</sup>C]Methylpyrrolidone in Male Sprague-Dawley Rats. A Saturable NMP Elimination Process

Payan, Jean-Paul; Beydon, Dominique; Fabry, J.; Boudry, Isabelle; Cossec, Benoît; Ferrari, Elisabeth

doi:10.1124/dmd.30.12.1418

Cited by 21 publications

(11 citation statements)

References 17 publications

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“…This is in accordance with results previously reported by Payan et al (2002). In that study five groups of rats were intravenously administered different doses of methyl labelled 14 C-NMP and urinary elimination of 5-HNMP accounted for 42-55% of the administered doses.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, in this study 99-100% of the eliminated amount (51-58% of the dose) was found within 24 h of the administration. Payan et al (2002) reported similar results, 85-98% of the radioactivity in urine. However, for the two highest administrations (100 and 500 mg/kg) in that study, an increased amount was eliminated in urine post 24 h, indicating that there was a delay in urinary elimination.…”

Section: Discussionsupporting

confidence: 64%

“…However, there were no obvious evidence for accumulation but since only urine was sampled in this study it is not possible to draw a certain conclusion. Still ,we think that the lack of tissue distributed radioactivity in other studies (Wells and Digenis, 1988;Midgley et al, 1992) together with the rapid elimination of radioactivity found by Payan et al (2002) indicate no or only little accumulation. In humans, repeated exposure to NMP will result in an accumulation of at least 2-HMSI due to its long half-life (Jönsson and Åkesson, 2003).…”

Section: Discussionmentioning

confidence: 67%

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Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats

Carnerup

Saillenfait

Jönsson

2005

Food and Chemical Toxicology

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The primary aims were to study the metabolism in rats and to determine the biological levels after one oral developmentally toxic dose of N-methyl-2-pyrrolidone (NMP), a widely used industrial chemical. Non-pregnant female Sprague-Dawley rats were given an oral single dose of either a non-toxic dose of 125 mg NMP/kg (group 1) by gavage or a developmentally toxic dose of 500 mg/kg (group 2). Blood plasma (7 rats per time point) and urine (10 rats per time point) were sampled up to 72h after administration and analyzed using mass spectrometry. In both plasma and urine NMP, 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP), N-methylsuccinimide and 2-hydroxy-N-methylsuccinimide (2-HMSI) and 2-pyrrolidone (2-P) were identified. In urine 48% of the administered dose was recovered as 5-HNMP and 2-5% as 2-HMSI. The total recovery in urine was 53-59%. The peak concentrations for NMP in plasma were 1.2 and 6.9 mmol/l, 0.42 and 0.76 mmol/l for 5-HNMP, 0.07 and 0.31 mmol/l for MSI and for 2-HMSI the concentrations were 0.02 and 0.05 mmol/l for group 1 and 2, respectively. In summary, the same metabolites were found in rats as in humans and the biological levels were reported for NMP and its metabolites after oral exposure to a developmentally toxic dose and one non-toxic dose of NMP.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 67%

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Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats

Carnerup

Saillenfait

Jönsson

2005

Food and Chemical Toxicology

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“…However, 6 hr after intravenous injection of NMP, the highest 14 C‐NMP radioactivity was detected in the liver, intestine, testes, stomach, and kidney, but 24 hr after injection it was measured only in liver and intestines (Åkesson and Jonsson, ; Åkesson and Paulsson, ; Wells and Digenis, ; Sitarek and Kilanowicz, ). Main NMP metabolite is 5‐hydroxy‐N‐methylpyrrolidone, which was detected in rats administered 14 C‐NMP intravenously (Payan et al, ).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Reproductive Disorders in Female Rats Exposed to N‐Methyl‐2‐Pyrrolidone

Sitarek

Stetkiewicz²,

Wąsowicz³

2012

Birth Defects Research Pt B

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Fertility index did not significantly differ in the control and the group exposed at 150 mg/kg/day but it was significantly lower in the groups exposed at 450 or 1000 mg/kg/day. The number of live pups in the group exposed to the highest dose was significantly lower and the number of stillbirths in litters was significantly greater. Survival of the pups from all exposed groups during the 3 weeks after birth was significantly lower than the control animals. The results of our study indicate that intragastric exposure of female rats to NMP before pregnancy during gestation causes significant impairment in female fertility and intrauterine mortality rates. At lower doses, toxic or slightly toxic to the mothers, this substance causes decrease in viability and physical development of progeny.

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“…Elimination: The main elimination route for NMP and its metabolites is via the kidney through urinary excretion [136]. The elimination of NMP is a saturable process, and unchanged NMP is intensively reabsorbed by the glomeruli [138]. Despite extensive NMP toxicity studies performed on living organisms, including mice [140,141],rats [140][141][142][143][144][145][146][147][148], dogs [149],and humans [150][151][152][153][154][155][156][157], there are few studies documenting the toxicity of NMP with respect to subcutaneous or muscular toxicity.…”

Section: Physicochemical Propertiesmentioning

confidence: 99%

In vitro and in vivo studies of controlled release of novel peptide from in situ polymer precipitation delivery system

Lim¹

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The in situ polymer precipitation delivery system has generated much interest over the last two decades. The ease of manufacturing and administering the delivery system are key advantages that have contributed to its increasing preference as a mode of drug delivery. Although much research has been performed on this system, the number of studies that have translated into animal models and subsequently into clinical trials is much lower than desired. This study aimed to investigate and understand the release mechanism and kinetics involved in peptide release from an in situ polymer precipitation system. Moreover, this study aimed to establish a correlation between the in vitroand in vivo-derived data. The ultimate aim was to identify a delivery system that can be used to deliver a novel therapeutic peptide, CD-NP, for the treatment of heart failure conditions. This study can be divided into 3 broad categories. First, in vitro studies were performed to characterise systemically the delivery system and its efficacy at achieving the prolonged release of the drug Cenderitide. Various gel formulation parameters were tested, i.e., the effect of polymer concentration, co-solvent, drug-loading and injected volume. The co-solvent system using the gel formulation 40% PLGA / 40% NMP / 20% triacetin was the most suitable for achieving the desired linear peptide release profile. Investigation of the solvent efflux and its influence on the drug release profile and shell structure formation morphology were also investigated. The Abstract x | P a g e solvent efflux and shell structure formation were found to be interdependent and affected the drug release profile. Second, feasibility studies were performed on both healthy and diseased Wistar rats. As

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Toxicokinetics and Metabolism ofN-[¹⁴C]Methylpyrrolidone in Male Sprague-Dawley Rats. A Saturable NMP Elimination Process

Cited by 21 publications

References 17 publications

Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats

Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats

Evaluation of Reproductive Disorders in Female Rats Exposed to N‐Methyl‐2‐Pyrrolidone

In vitro and in vivo studies of controlled release of novel peptide from in situ polymer precipitation delivery system

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Toxicokinetics and Metabolism ofN-[14C]Methylpyrrolidone in Male Sprague-Dawley Rats. A Saturable NMP Elimination Process

Cited by 21 publications

References 17 publications

Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats

Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats

Evaluation of Reproductive Disorders in Female Rats Exposed to N‐Methyl‐2‐Pyrrolidone

In vitro and in vivo studies of controlled release of novel peptide from in situ polymer precipitation delivery system

Contact Info

Product

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Toxicokinetics and Metabolism ofN-[¹⁴C]Methylpyrrolidone in Male Sprague-Dawley Rats. A Saturable NMP Elimination Process