Vehicle-dependent disposition kinetics of fluoranthene in Fisher-344 rats

Abstract

The objective of this study was to evaluate how the vehicles of choice affect the pharmacokinetics of orally administered Fluoranthene [FLA] in rats. Fluoranthene is a member of the family of Polycyclic Aromatic Hydrocarbon chemicals. Fluoranthene exposure to humans may occur as a result of cigarette smoking, consumption of contaminated food and water, heating woods in stoves and boilers, industrial sources such as coal gasification, carbon and graphite electrode manufacturing. Adult male Fisher-344 rats were given single oral doses of 25 and 50 microg/kg FLA in tricaprylin, peanut oil, cod liver oil, Tween 80/isotonic saline (1:5) and 2% Alkamuls-EL620 through gavage. After administration, the rats were housed individually in metabolic cages and sacrificed at 2, 4, 6, 8, 10 and 12 hours post FLA exposure. Blood, lung, liver, small intestine, adipose tissue samples, urine, and feces were collected at each time point. Samples were subjected to a liquid-liquid extraction using methanol, chloroform, and water. The extracts were analyzed by a reverse-phase HPLC, equipped with a fluorescence detector. The results revealed a dose-dependent increase in FLA concentrations in plasma and tissues for all the vehicles used. Plasma and tissue FLA concentrations were greater for peanut oil; cod liver oil, and tricaprylin vehicles compared to Alkamuls (p < 0.05), and Tween 80/isotonic saline (1:5). Most of the FLA administered through peanut oil, cod liver oil and tricaprylin was cleared from the body by 8 hours (90%) and 12 hours (80%) post administration for the 25 microg/kg and 50 microg/kg dose groups, respectively. With both doses employed, the metabolism of FLA was highest when cod liver oil was used as a vehicle and lowest in vehicles containing detergent/water [cod liver oil > peanut oil > tricaprylin > alkamuls > Tween 80/isotonic saline (1:5)]. These findings suggest that uptake and elimination of FLA is accelerated when administered through oil-based vehicles. The low uptake of FLA from Alkamuls and Tween 80/isotonic saline may have been a result of the poor solubility of the chemical. In summary, our findings reiterate that absorption characteristics of FLA were governed by the dose as well as the dosing vehicle. The vehicle-dependent bioavailability of FLA suggests a need for the judicious selection of vehicles in evaluating oral toxicity studies for risk assessment purposes.

Figure 1:

Effect of dosing vehicle on time-course distribution of unmetabolized fluoranthene (FLA) in plasma, jejunum, and feces of F-344 rats that received 25 μg FLA/kg body wt. via oral gavage. Values represent mean ± SE (n = 6). Asterisks denote statistical significance (p < 0.05) at the respective time point compared to 2 hour post-exposure.

Figure 2:

Effect of dosing vehicle on time-course distribution of unmetabolized fluoranthene (FLA) in plasma, jejunum, and feces of F-344 rats that received 50 μg FLA/kg body wt. via oral gavage. Values represent mean ± SE (n = 6). Asterisks denote statistical significance (p < 0.05) at the respective time point compared to 2 hour post-exposure.

Figure 3:

Effect of dosing vehicle on time-course distribution of fluoranthene (FLA) metabolite concentrations in plasma, jejunum, feces, liver, lung, adipose, urine and feces of F-344 rats that received 25 μg FLA/kg body wt. via oral gavage. Values represent mean ± SE (n = 6). Asterisks denote statistical significance (p < 0.05) at the respective time point compared to 2 hour post-exposure.

Figure 4:

Effect of dosing vehicle on time-course distribution of fluoranthene (FLA) metabolite concentrations in plasma, jejunum, feces, liver, lung, adipose, urine and feces of F-344 rats that received 50 μg FLA/kg body wt. via oral gavage. Values represent mean ± SE (n = 6). Asterisks denote statistical significance (p < 0.05) at the respective time point compared to 2 hour post-exposure.