Advertisement

Toxicokinetics of N-ethyl-2-pyrrolidone and its metabolites in blood, urine and amniotic fluid of rats after oral administration

  • Daniel Bury
  • Anne Marie Saillenfait
  • Fabrice Marquet
  • Heiko U. KäfferleinEmail author
  • Thomas Brüning
  • Holger M. Koch
Toxicokinetics and Metabolism
  • 25 Downloads

Abstract

The toxicokinetics of N-ethyl-2-pyrrolidone (NEP), an embryotoxic organic solvent, has been studied in Sprague–Dawley rats after oral exposure. NEP and its metabolites 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI) were measured in plasma of pregnant and non-pregnant rats, and fetuses after NEP administration by gavage for 14 consecutive days at 50 mg/kg/day, and in plasma of non-pregnant rats after a single NEP administration. Additionally, amniotic fluid and 24-h urine samples of the pregnant rats were analyzed for NEP metabolites. Furthermore, 24-h urine samples from a repeated dose 28-day oral toxicity study in female (non-pregnant) and male rats administered developmentally non-toxic (0, 5, and 50 mg/kg/day) or toxic (250 mg/kg/day) doses of NEP were analyzed. Median peak plasma concentrations in non-pregnant rats after a single dose and repeated doses were 551 and 611 (NEP), 182 and 158 (5-HNEP), and 63.8 and 108 µmol/L (2-HESI), respectively; whereas in pregnant rats and fetuses 653 and 619 (NEP), 80.5 and 91.7 (5-HNEP) and 77.3 and 45.7 µmol/L (2-HESI) were detected. Times to reach maximum plasma concentrations for NEP, 5-HNEP, and 2-HESI were 1, 4, and 8 h, respectively, and were comparable to N-methyl-2-pyrrolidone (NMP) and its corresponding metabolites. In pregnant rats, plasma elimination of NEP and metabolite formation/elimination was much slower compared to non-pregnant rats and efficient placental transfer of NEP was observed. Our data, overall, suggest differences in the toxicokinetics of chemicals between pregnant and non-pregnant rats which need to be addressed in risk assessment, specifically when assessing developmental toxicants such as NEP.

Keywords

N-Ethyl-2-pyrrolidone (NEP) Toxicokinetics Rats Plasma Urine Amniotic fluid 

Notes

Acknowledgements

This study was core-funded by the German Social Accident Insurances (DGUV) and the French National Research and Safety Institute (INRS). We would like to thank Stephanie Zülz and Eleonore Menne for excellent technical assistance.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The animal facilities used in the study have been accredited by the French Ministry of Agriculture. All animal experiments complied with European Union Directive 2010/63/EU and French legislation for the protection of animals used for scientific purposes and were approved by the local ethical committee and the French Ministry of Superior Education and Research.

Supplementary material

204_2019_2404_MOESM1_ESM.docx (140 kb)
Supplementary material 1 (DOCX 139 KB)

References

  1. Åkesson B, Jönsson BA (1997) Major metabolic pathway for N-methyl-2-pyrrolidone in humans. Drug Metabol Dispos 25:267–269Google Scholar
  2. Boike GM, Deppe G, Young JD, Gove NL, Bottoms SF, Malone JM, Malviya VK, Sokol RJ (1989) Chemotherapy in a pregnant rat model. Gynecol Oncol 34:187–190CrossRefGoogle Scholar
  3. Byers JP, Sarver JG (2009) Pharmacokinetic modeling. In: Hacker MP, Messer WS, Bachmann KA (eds) Pharmacology. Principles and practice. Elsevier/Academic Press, Amsterdam, pp 201–277Google Scholar
  4. Carnerup MA, Saillenfait AM, Jönsson BAG (2005) Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats. Food Chem Toxicol 43:1441–1447CrossRefGoogle Scholar
  5. Carpenter SP, Savage DD, Schultz ED, Raucy JL (1997) Ethanol-mediated transplacental induction of CYP2E1 in fetal rat liver. J Pharmacol Exp Therap 282:1028–1036Google Scholar
  6. EC, European Commission (2013) Commission Regulation No 944/2013 of October 2013 amending, for the purposes of its adaptation to technical and scientific progress, Regulation No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixturesGoogle Scholar
  7. Flick B, Talsness CE, Jäckh R, Buesen R, Klug S (2009) Embryotoxic potential of N-methyl-pyrrolidone (NMP) and three of its metabolites using the rat whole embryo culture system. Toxicol Appl Pharmacol 237:154–167CrossRefGoogle Scholar
  8. He XJ, Ejiri N, Nakayama H, Doi K (2005) Effects of pregnancy on CYPs protein expression in rat liver. Exp Mol Pathol 78:64–70CrossRefGoogle Scholar
  9. Hines RN (2008) The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Therap 118:250–267CrossRefGoogle Scholar
  10. Johnsrud EK, Koukouritaki SB, Divakaran K, Brunengraber LL, Hines RN, McCarver DG (2003) Human hepatic CYP2E1 expression during development. J Pharm Exp Therap 307:402–407CrossRefGoogle Scholar
  11. Koch HM, Bader M, Weiss T, Koslitz S, Schütze A, Käfferlein HU, Brüning T (2014) Metabolism and elimination of N-ethyl-2-pyrrolidone (NEP) in human males after oral dosage. Arch Toxicol 88:893–899CrossRefGoogle Scholar
  12. Koslitz S, Meier S, Schindler BK, Weiss T, Koch HM, Brüning T, Käfferlein HU (2014) Biomonitoring of N-ethyl-2-pyrrolidone in automobile varnishers. Toxicol Lett 231:142–146CrossRefGoogle Scholar
  13. Krauer B (1987) Physiological changes and drug disposition during pregnancy. In: Nau H, Scott WJ (eds) Pharmacokinetics in teratogenesis: interspecies comparison and maternal/embryonic-fetal drug transfer, vol 1. CRC Press, Boca Raton, pp 3–12Google Scholar
  14. Ligocka D, Lison D, Haufroid V (2003) Contribution of CYP2E1 to N-methyl-2-pyrrolidone metabolism. Arch Toxicol 77:261–266CrossRefGoogle Scholar
  15. Payan JP, Saillenfait AM, Beydon D, Ban M, de Ceaurriz J (1990) Pregnancy-associated changes in renal toxicity of cadmium-metallothionein: Possible role of intracellular metallothionein. Toxicology 65:223–232CrossRefGoogle Scholar
  16. Payan JP, Beydon D, Fabry JP, Boudry I, Cossec B, Ferrari E (2002) Toxicokinetics and metabolism of N-[14C]-methylpyrrolidone in male Sprague–Dawley rats. A saturable NMP elimination process. Drug Metabol Dispos 30:1418–1424CrossRefGoogle Scholar
  17. Rowland M, Tozer TN (2002) Clinical pharmacokinetics: concepts and applications, 3rd edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  18. Saillenfait AM, Gallissot F, Sabaté JP (2007a) Developmental toxic effects of N-ethyl-2-pyrrolidone administered orally to rats. J Appl Toxicol 27:491–497CrossRefGoogle Scholar
  19. Saillenfait AM, Sabaté JP, Gallissot F (2007b) Comparative developmental toxicities of the three major metabolites of N-methyl-2-pyrrolidone after oral administration in rats. J Appl Toxicol 27:571–581CrossRefGoogle Scholar
  20. Saillenfait AM, Marquet F, Sabaté JP, Ndiaye D, Lambert-Xolin AM (2016) 4-Week repeated dose oral toxicity study of N-ethyl-2-pyrrolidone in Sprague Dawley rats. Regul Toxicol Pharmacol 81:275–283CrossRefGoogle Scholar
  21. Schindler BK, Koslitz S, Meier S, Belov VN, Koch HM, Weiss T, Brüning T, Käfferlein HU (2012) Quantification of four major metabolites of embryotoxic N-methyl- and N-ethyl-2-pyrrolidone in human urine by cooled-injection gas chromatography and isotope dilution mass spectrometry. Anal Chem 84:3787–3794CrossRefGoogle Scholar
  22. Toutain PL, Bousquet-Mélou A (2004) Plasma clearance. J Vet Pharmacol Therap 27:415–425CrossRefGoogle Scholar
  23. UBA, Umweltbundesamt (2015) Stoffmonographie für N-Ethyl-2-pyrrolidon (NEP) und Human-Biomonitoring (HBM)-Werte für die Metaboliten 5-Hydroxy-NEP (5-HNEP) und 2-Hydroxy-N-ethylsuccinimid (2-HESI) im Urin. Bundesgesundheitsbl 58:1041–1052CrossRefGoogle Scholar
  24. Ulrich N, Bury D, Koch HM, Rüther M, Weber T, Käfferlein HU, Weiss T, Brüning T, Kolossa-Gehring M (2018) Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24 h urine samples of the German Environmental Specimen Bank from 1991 to 2014. Int Arch Occup Environ Health 91:1073–1082CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute for Prevention and Occupational Medicine of the German Social Accident InsuranceInstitute of the Ruhr-University Bochum (IPA)BochumGermany
  2. 2.National Research and Safety InstituteVandoeuvre CedexFrance

Personalised recommendations