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© 1984 Oxford University Press

research-article

Age-Dependent Pharmacokinetic Changes of Ethylenediamine in Fischer 344 Rats Parallel to a Two-Year Chronic Toxicity Study1

RAYMOND S. H. YANG2,, MARILYN J. TALLANT and JOHN A. MCKELVEY

Bushy Run Research Center, Mellon Institute-Union Carbide Corporation, R.D 4. Mellon Road, Export, Pennsylvania 15632

Age-Dependent Pharmacokinetic Changes of Ethylenediamine in Fischer 344 Rats Parallel to a Two-Year Chronic Toxicity Study. YANG, R. S. H., TALLANT, M. J., AND MCKELVEY, J. A. (1984). Fundam. Appl. Toxicol. 4, 663–670. As part of a 2-year chronic toxicity study, the phannacokinetics of ethylenediamine (EDA) was studied in Fischer 344 rats of both sexes at day zero (naive animals), 6 months (controls and high level animals), and 18 months (controls and high level animals). The rats, which were randomized along with the rest of the animals on the toxicity study, were taken for pharmacokinetic experiments at the specified time. A single per os (po) dose of 50 mg [14C]EDA - 2HCI/kg was given to each rat and the plasma kinetics was followed for a 24-hr period. Five pharmacokinetic parameters (absorption rate constant, terminal half-life, area under the curve, volume of distribution, and l4CO2 production rate constant) were compared with respect to age, sex, and chronic dosing. There were no apparent age-, sex-, and/or chronic dosing-related differences in absorption rate constant and terminal half-life. However, age-related changes in area under the curve (AUC) were evident. The older rats had higher values (generally two- to threefold) for AUC than the younger rats. This age-related difference in AUC is closely associated with the volumes of distribution (Vd of the animals of varying ages. On the basis of liters per kilogram, the Vd's of the older rats are approximately one-fourth to one-half of those for the younger (zero day) rats. The 14CO2 production rate constant was derived from the rate of formation of 14CO2 as a result of [14C]EDA - 2HCl dosing. The comparison of this constant under the various experimental conditions suggests sex-related differences. The findings of this study demonstrated age-, and to a lesser extent, sex-related differences. Chronic dosing-related changes are minimal These results are discussed in light of the chronic toxicity findings.


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