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Sex Differences in the Single-Dose Toxicokinetics of N-Nitrosomethyl(2-hydroxyethyl)amine in the Rat¹

Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute [A. J. S., R. W. N., Y-H. H., L. K. K.] and Chemical Synthesis and Analysis Laboratory, Program Resources, Inc. [J. A. H.], Frederick Cancer Research Facility, Frederick, Maryland 21701

The single-dose toxicokinetics of N-nitrosomethyl(2-hydroxyethyl)amine (NMHA) has been characterized in 8-week-old 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 male rats revealed biphasic first-order elimination with a terminal half-life of 37.4 ± 1.7 min for unchanged NMHA and 101 ± 6 min for total radioactivity, and extensive conversion to polar metabolites was seen in the high-performance liquid chromatographic assays. The systemic blood clearance and apparent steady-state volume of distribution for unchanged NMHA were 13.1 ± 0.9 ml/min/kg and 685 ± 31 ml/kg, respectively. Renal blood clearance and intrinsic hepatic clearance were estimated to be 0.805 ± 0.024 and 16.7 ± 2.1 ml/min/kg, respectively. A similar dose given to female rats yielded a terminal half-life for NMHA of 27.2 ± 1.2 min, a steady-state volume of distribution of 652 ± 23 ml/kg, and systemic blood, renal blood, and intrinsic hepatic clearances of 16.9 ± 1.3, 1.45 ± 0.14, and 22.5 ± 0.3 ml/min/kg, respectively. The sex differences in terminal half-life and systemic blood, renal blood, and intrinsic hepatic clearances were significant at the P < 0.05 level. Larger doses given by gavage, which appeared to be completely absorbed from the gut, indicated systemic bioavailabilities for unchanged NMHA of 78 ± 10% and 69 ± 1% for male and female rats, respectively. Binding of NMHA to plasma proteins was found to be negligible. Taken together the data allow for the conclusion that the observed sex differences in toxicokinetic parameters are due to differences in the intrinsic hepatic clearance of the compound. This difference in the ability of the liver to metabolize NMHA in vivo correlates with and may contribute to the greater susceptibility of female rats to hepatocarcinogenesis and of male rats to development of tumors in the nasal epithelium following oral exposure to NMHA.

¹ This work was supported in part by NCI contract number NO1-CO-74102 to Program Resources, Inc.

² To whom requests for reprints should be addressed, at NCI-FCRF, Bldg. 538, Frederick, MD 21701.

Received 7/12/88. Revised 11/22/88. Accepted 12/29/88.