Inhalation pharmacokinetics based on gas uptake studies. VI. Comparative evaluation of ethylene oxide and butadiene monoxide as exhaled reactive metabolites of ethylene and 1,3-butadiene in rats.

Abstract

When ethylene oxide or butadiene monoxide is added to the atmosphere of a closed inhalation chamber occupied by Sprague-Dawley rats, a first-order elimination pattern is observed. When either of these compounds is IP injected into rats which are subsequently placed in the closed chamber, the course of epoxide in the atmosphere follows Bateman exponential functions. From the experimental data, the kinetic parameters for distribution and metabolic elimination of ethylene oxide and butadiene monoxide can be derived. When ethylene or 1,3-butadiene was added to the closed exposure systems and kept at atmospheric concentrations which assured maximal metabolic turnover of the olefin (i.e., concentrations above 1,000 ppm ethylene or 1,500 ppm 1,3-butadiene), exhalation of the appropriate epoxide occurred and led finally to a constant (plateau) concentration of the reactive metabolite in the system's atmosphere. Although the initial time-course was different between butadiene monoxide and ethylene oxide (with a high initial increase of ethylene oxide and a subsequent decrease) an analysis at steady-state (plateau concentrations) revealed that only 29% of the amounts of both epoxides which in theory are formed as primary metabolites from the parent olefins are systematically available (i.e., distributed in the entire organism). The discrepancy is probably related to first pass elimination of the epoxide.