DISPOSITION OF BUTADIENE EPOXIDES IN SPRAGUE-DAWLEY RATS

1,2-Epoxybutene (BMO) and diepoxybutane (BDE) are metabolic products o f 1,3-butadiene in rodents. Both BMO and BDE are suspect in the develo pment of tumors in rats and mice. To understand the distribution and e limination of these compounds in the absence of the rate-limiting prod uction from butadiene, the pharmacokinetics of BMO and BDE in blood we re determined in adult male Sprague-Dawley rats following intravenous administration. All animals were dually cannulated in these studies. F or the BMO studies, rats were dosed with 71, 143, or 286 mu mol/kg BMO (n = 3 for each dose group). For the BDE studies, rats were dosed wit h 523 mu mol/kg BDE (n = 3). All animals tolerated the BMO and BDE dos es without grossly observable adverse effects. Blood was drawn at pred etermined time points and extracted in methylene chloride. BDE and BMO concentrations were quantitated by gas chromatography or gas chromato grapy/mass spectrometry. The BMO distribution half-lives were short an d ranged from 1.4 min at the lowest dose to 1.8 min at the highest dos e. Volume of distribution at steady state ranged from 0.53 +/- 0.17 to 0.59 +/- 0.31 1/kg. Systemic clearances ranged from 67 +/- 17 to 114 +/- 20 ml/min per kg. The terminal elimination half-lives were also sh ort and ranged from 5.7 to 8.5 min among the doses, The pharmacokineti c parameters after an i.v. dose of 523 mu mol/kg BDE were a distributi on half-life of 2.7 min, terminal elimination T-1/2 of 14 min, volume of distribution at steady state of 0.73 +/- 0.06 1/kg, and systemic cl earance of 76 +/- 8 ml/min per kg. These pharmacokinetic parameters de monstrate the similarity between disposition of the two epoxides in ra ts, that include a rapid distribution after i.v. administration into a small extravascular body compartment as well as a rapid elimination f rom blood. These pharmacokinetic data provide useful blood clearance i nformation for assessing the critical physiological and biochemical de terminants underlying the disposition of butadiene epoxides. (C) 1997 Elsevier Science Ireland Ltd.