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Disposition of butadiene epoxides in Sprague-Dawley rats
J L Valentine1, P J Boogaard, L M Sweeney
1Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.
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.
Insights
This study investigated the pharmacokinetics of 1,2-epoxybutene (BMO) and diepoxybutane (BDE) in rats. Both BMO and BDE showed rapid distribution and elimination from blood, indicating similar disposition patterns.
Area of Science:
- Toxicology
- Pharmacokinetics
- Metabolism
Background:
- 1,2-Epoxybutene (BMO) and diepoxybutane (BDE) are toxic metabolites of 1,3-butadiene.
- These epoxides are suspected carcinogens in rodents, implicated in tumor development.
- Understanding their distribution and elimination is crucial for assessing butadiene toxicity.
Purpose of the Study:
- To determine the pharmacokinetics of BMO and BDE in rats.
- To elucidate the distribution and elimination profiles of these butadiene metabolites in blood.
- To provide data for assessing the physiological determinants of butadiene epoxide disposition.
Main Methods:
- Adult male Sprague-Dawley rats were intravenously administered BMO or BDE.
- Blood samples were collected at predetermined time points post-administration.
- BMO and BDE concentrations were quantified using gas chromatography and gas chromatography/mass spectrometry.
Main Results:
- BMO exhibited short distribution half-lives (1.4–1.8 min) and terminal elimination half-lives (5.7–8.5 min).
- BDE showed a distribution half-life of 2.7 min and a terminal elimination half-life of 14 min.
- Both epoxides demonstrated rapid distribution into a small extravascular compartment and swift blood elimination.
Conclusions:
- The pharmacokinetic profiles of BMO and BDE in rats are similar.
- Both compounds undergo rapid distribution and elimination from the blood.
- These findings offer critical insights into the disposition of butadiene epoxides.