Disposition of butadiene epoxides in Sprague-Dawley rats. 1997

J L Valentine, and P J Boogaard, and L M Sweeney, and M J Turner, and J A Bond, and M A Medinsky
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.

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.

UI MeSH Term Description Entries
D007275 Injections, Intravenous Injections made into a vein for therapeutic or experimental purposes. Intravenous Injections,Injection, Intravenous,Intravenous Injection
D008297 Male Males
D008401 Gas Chromatography-Mass Spectrometry A microanalytical technique combining mass spectrometry and gas chromatography for the qualitative as well as quantitative determinations of compounds. Chromatography, Gas-Liquid-Mass Spectrometry,Chromatography, Gas-Mass Spectrometry,GCMS,Spectrometry, Mass-Gas Chromatography,Spectrum Analysis, Mass-Gas Chromatography,Gas-Liquid Chromatography-Mass Spectrometry,Mass Spectrometry-Gas Chromatography,Chromatography, Gas Liquid Mass Spectrometry,Chromatography, Gas Mass Spectrometry,Chromatography, Mass Spectrometry-Gas,Chromatography-Mass Spectrometry, Gas,Chromatography-Mass Spectrometry, Gas-Liquid,Gas Chromatography Mass Spectrometry,Gas Liquid Chromatography Mass Spectrometry,Mass Spectrometry Gas Chromatography,Spectrometries, Mass-Gas Chromatography,Spectrometry, Gas Chromatography-Mass,Spectrometry, Gas-Liquid Chromatography-Mass,Spectrometry, Mass Gas Chromatography,Spectrometry-Gas Chromatography, Mass,Spectrum Analysis, Mass Gas Chromatography
D009153 Mutagens Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. Clastogen,Clastogens,Genotoxin,Genotoxins,Mutagen
D012015 Reference Standards A basis of value established for the measure of quantity, weight, extent or quality, e.g. weight standards, standard solutions, methods, techniques, and procedures used in diagnosis and therapy. Standard Preparations,Standards, Reference,Preparations, Standard,Standardization,Standards,Preparation, Standard,Reference Standard,Standard Preparation,Standard, Reference
D002273 Carcinogens Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. Carcinogen,Oncogen,Oncogens,Tumor Initiator,Tumor Initiators,Tumor Promoter,Tumor Promoters,Initiator, Tumor,Initiators, Tumor,Promoter, Tumor,Promoters, Tumor
D002849 Chromatography, Gas Fractionation of a vaporized sample as a consequence of partition between a mobile gaseous phase and a stationary phase held in a column. Two types are gas-solid chromatography, where the fixed phase is a solid, and gas-liquid, in which the stationary phase is a nonvolatile liquid supported on an inert solid matrix. Chromatography, Gas-Liquid,Gas Chromatography,Chromatographies, Gas,Chromatographies, Gas-Liquid,Chromatography, Gas Liquid,Gas Chromatographies,Gas-Liquid Chromatographies,Gas-Liquid Chromatography
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004852 Epoxy Compounds Organic compounds that include a cyclic ether with three ring atoms in their structure. They are commonly used as precursors for POLYMERS such as EPOXY RESINS. Epoxide,Epoxides,Epoxy Compound,Oxiranes,Compound, Epoxy,Compounds, Epoxy
D006207 Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Halflife,Half Life,Half-Lifes,Halflifes

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