title: Disposition of butadiene epoxides in Sprague-Dawley rats.
abstract: 1,2-Epoxybutene (BMO) and diepoxybutane (BDE) are metabolic products of 1,3-butadiene in rodents. Both BMO and BDE are suspect in the development of tumors in rats and mice. To understand the distribution and elimination of these compounds in the absence of the rate-limiting production from butadiene, the pharmacokinetics of BMO and BDE in blood were determined in adult male Sprague-Dawley rats following intravenous administration. All animals were dually cannulated in these studies. For the BMO studies, rats were dosed with 71, 143, or 286 mumol/kg BMO (n = 3 for each dose group). For the BDE studies, rats were dosed with 523 mumol/kg BDE (n = 3). All animals tolerated the BMO and BDE doses without grossly observable adverse effects. Blood was drawn at predetermined time points and extracted in methylene chloride. BDE and BMO concentrations were quantitated by gas chromatography or gas chromatography/mass spectrometry. The BMO distribution half-lives were short and ranged from 1.4 min at the lowest dose to 1.8 min at the highest dose. Volume of distribution at steady state ranged from 0.53 +/- 0.17 to 0.59 +/- 0.31 l/kg. Systemic clearances ranged from 67 +/- 17 to 114 +/- 20 ml/min per kg. The terminal elimination half-lives were also short and ranged from 5.7 to 8.5 min among the doses. The pharmacokinetic parameters after an i.v. dose of 523 mumol/kg BDE were a distribution half-life of 2.7 min, terminal elimination T1/2 of 14 min, volume of distribution at steady state of 0.73 +/- 0.06 l/kg, and systemic clearance of 76 +/- 8 ml/min per kg. These pharmacokinetic parameters demonstrate the similarity between disposition of the two epoxides in rats, that include a rapid distribution after i.v. administration into a small extravascular body compartment as well as a rapid elimination from blood. These pharmacokinetic data provide useful blood clearance information for assessing the critical physiological and biochemical determinants underlying the disposition of butadiene epoxides.
authors.affiliation: Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Valentine
authors.forename: P J
authors.initials: PJ
authors.lastname: Boogaard
authors.forename: L M
authors.initials: LM
authors.lastname: Sweeney
authors.forename: M J
authors.initials: MJ
authors.lastname: Turner
authors.forename: J A
authors.initials: JA
authors.lastname: Bond
authors.forename: M A
authors.initials: MA
authors.lastname: Medinsky
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002849:Chromatography, Gas; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006400:Hematocrit; D007275:Injections, Intravenous; D008297:Male; D009153:Mutagens / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D012984:Software
chemical_list: D002273:Carcinogens; D004852:Epoxy Compounds; D009153:Mutagens; C024370:3,4-epoxy-1-butene; C007366:diepoxybutane