caa a22 4500 467979189 CHVBK 20180323112514.0 cr unu---uuuuu 170328e19900301xx s 000 0 eng 10.1007/BF01974395 doi (NATIONALLICENCE)springer-10.1007/BF01974395 Single-dose toxicokinetics of N -nitrosomethylethylamine and N -nitrosomethyl (2,2,2-trideuterioethyl)amine in the rat [Elektronische Daten] [Anthony Streeter, Raymond Nims, Lucy Anderson, Young-Hun Heur, Eric von Hofe, Paul Kleihues, Victor Nelson, Bruce Mico, Larry Keefer] To investigate the origins of an organotropic shift toward increasing esophageal carcinogenicity and DNA alkylation caused by β-trideuteration of the hepatocarcinogen,N-nitrosomethylethylamine (NMEA), the single-dose toxicokinetics of NMEA andN-nitrosomethyl(2,2,2-trideuterioethyl)amine (NMEA-d 3) has been characterized in 8-week-old male Fischer 344 rats by analysis using high performance liquid chromatography of serial blood samples. An i.v. bolus dose of 0.6 μmol/kg to rats revealed biphasic first order elimination with a terminal half-life of 9.46 ± 0.69 min for unchanged NMEA and 28.9 ± 2.4 min for total radioactivity. Extensive conversion to polar metabolites was observed in the chromatograms. The systemic blood clearance and apparent steadystate volume of distribution for unchanged NMEA were 39.9 ± 4.6 ml/min/kg and 496 ± 36 ml/kg, respectively. There was negligible plasma protein binding and no detectable NMEA was excreted unchanged in the urine. Larger doses given by gavage indicated a systemic bioavailability of 25 ± 1%. Similar doses of NMEA-d 3 given to other groups of rats revealed no significant differences in any of the toxicokinetic parameters. NoN-nitrosomethyl (2-hydroxyethyl)amine was found as a detectable metabolite of NMEA or NMEA-d 3 in any of the blood or urine samples which were analyzed. When considered together, the data suggest that previously observed differences in organ specificity for the carcinogens, NMEA and NMEA-d 3, are not due to differences in the total amounts of nitrosamine reaching particular tissues, but may have other localized causes such as differences in the enzymes responsible for metabolism which are present in each tissue. Such differences may make too small a contribution to the total systemic clearance to be detectable in that parameter, but at the level of the fraction of a dose that alkylates DNA they may be important. Springer-Verlag, 1990 N -Nitrosomethylethylamine nationallicence Deuterium isotope effect nationallicence N -Nitrosomethyl(2,2,2-trideuterioethyl)amine nationallicence Toxicokinetics nationallicence Rat nationallicence NMEA : N-nitrosomethylethylamine nationallicence [14C]NMEA : N-nitroso[14C]methylethylamine nationallicence NMEA- d 3 : N-nitrosomethyl(2,2,2,-trideuterioethyl)amine nationallicence [14C]NMEA- d 3 : N-nitroso[14C]methyl(2,2,2-trideuterioethyl)amine nationallicence NMHA : N-nitrosomethyl(2-hydroxyethyl)amine nationallicence NDMA : N-nitrosodimethylamine nationallicence i.g. : intragastric nationallicence t : time nationallicence C : concentration nationallicence A, B and G : coefficients of the exponential terms which describe the change in blood concentration over time nationallicence α, β and γ : first order rate constants for the distribution, elimination or absorption phases nationallicence t 1/2(α), t 1/2(β) and t 1/2(γ) : half-lives of the distribution, elimination, or absorption phases nationallicence AUC : area under the blood concentration versus time curve nationallicence Cl : systemic blood clearance nationallicence F : systemic bioavailability nationallicence MRT : mean residence time nationallicence MAT : mean absorption time nationallicence Vss : apparent steady-state volume of distribution nationallicence HPLC : high performance liquid chromatography nationallicence TLC : thin layer chromatography nationallicence GC/MS : gas chromatography/mass spectrometry nationallicence Streeter Anthony Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut Nims Raymond Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut Anderson Lucy Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut Heur Young-Hun Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut von Hofe Eric Laboratory of Neuropathology, Department of Pathology, University of Zürich, CH-8091, Zürich, Switzerland aut Kleihues Paul Laboratory of Neuropathology, Department of Pathology, University of Zürich, CH-8091, Zürich, Switzerland aut Nelson Victor Chemical Synthesis and Analysis Laboratory, Program Resources, Inc., Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut Mico Bruce Department of Drug Metabolism, Hoffmann-La Roche, Inc., 07110, Nutley, New Jersey, USA aut Keefer Larry Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut Archives of Toxicology Springer-Verlag 64/2(1990-03-01), 109-115 0340-5761 64:2<109 1990 64 204 https://doi.org/10.1007/BF01974395 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF01974395 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Streeter Anthony Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut NATIONALLICENCE 700 1- Nims Raymond Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut NATIONALLICENCE 700 1- Anderson Lucy Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut NATIONALLICENCE 700 1- Heur Young-Hun Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut NATIONALLICENCE 700 1- von Hofe Eric Laboratory of Neuropathology, Department of Pathology, University of Zürich, CH-8091, Zürich, Switzerland aut NATIONALLICENCE 700 1- Kleihues Paul Laboratory of Neuropathology, Department of Pathology, University of Zürich, CH-8091, Zürich, Switzerland aut NATIONALLICENCE 700 1- Nelson Victor Chemical Synthesis and Analysis Laboratory, Program Resources, Inc., Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut NATIONALLICENCE 700 1- Mico Bruce Department of Drug Metabolism, Hoffmann-La Roche, Inc., 07110, Nutley, New Jersey, USA aut NATIONALLICENCE 700 1- Keefer Larry Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, 21701, Frederick, Maryland, USA aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 64/2(1990-03-01), 109-115 0340-5761 64:2<109 1990 64 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer