Single-dose toxicokinetics ofN-nitrosomethylethylamine andN-nitrosomethyl (2,2,2-trideuterioethyl)amine in the rat

Abstract

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.