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.
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References
Åkesson B, Jönsson BA (1997) Major metabolic pathway for N-methyl-2-pyrrolidone in humans. Drug Metabol Dispos 25:267–269
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 34:187–190
Byers JP, Sarver JG (2009) Pharmacokinetic modeling. In: Hacker MP, Messer WS, Bachmann KA (eds) Pharmacology. Principles and practice. Elsevier/Academic Press, Amsterdam, pp 201–277
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 43:1441–1447
Carpenter SP, Savage DD, Schultz ED, Raucy JL (1997) Ethanol-mediated transplacental induction of CYP2E1 in fetal rat liver. J Pharmacol Exp Therap 282:1028–1036
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 mixtures
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 237:154–167
He XJ, Ejiri N, Nakayama H, Doi K (2005) Effects of pregnancy on CYPs protein expression in rat liver. Exp Mol Pathol 78:64–70
Hines RN (2008) The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Therap 118:250–267
Johnsrud EK, Koukouritaki SB, Divakaran K, Brunengraber LL, Hines RN, McCarver DG (2003) Human hepatic CYP2E1 expression during development. J Pharm Exp Therap 307:402–407
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 88:893–899
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 231:142–146
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 3–12
Ligocka D, Lison D, Haufroid V (2003) Contribution of CYP2E1 to N-methyl-2-pyrrolidone metabolism. Arch Toxicol 77:261–266
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 65:223–232
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 30:1418–1424
Rowland M, Tozer TN (2002) Clinical pharmacokinetics: concepts and applications, 3rd edn. Lippincott Williams & Wilkins, Philadelphia
Saillenfait AM, Gallissot F, Sabaté JP (2007a) Developmental toxic effects of N-ethyl-2-pyrrolidone administered orally to rats. J Appl Toxicol 27:491–497
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 27:571–581
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 81:275–283
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 84:3787–3794
Toutain PL, Bousquet-Mélou A (2004) Plasma clearance. J Vet Pharmacol Therap 27:415–425
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 58:1041–1052
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 91:1073–1082
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.
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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.
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Bury, D., Saillenfait, A.M., Marquet, F. et al. Toxicokinetics of N-ethyl-2-pyrrolidone and its metabolites in blood, urine and amniotic fluid of rats after oral administration. Arch Toxicol 93, 921–929 (2019). https://doi.org/10.1007/s00204-019-02404-x
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DOI: https://doi.org/10.1007/s00204-019-02404-x