Effect of dosing vehicle on the toxicity and metabolism of unsaturated aliphatic nitriles

Farooqui, Mohammed Y. H.; Ybarra, B.; Piper, J. Daniel; Tamez, Angel

doi:10.1002/jat.2550150512

Cited by 8 publications

(3 citation statements)

References 19 publications

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“…Fluoranthene has a tendency to be absorbed rapidly through saturated fat and its residence time in tissues was found to be high relative to that given through monounsaturated fat. Studies conducted by other investigators [23, 24] also found that the uptake of lipophilic environmental toxicants such as dioxins, furans and aliphatic nitriles through the GI tract is facilitated by the use of oils as dosing vehicles. Findings from the present study demonstrate that the solubility of FLA in the oil-based vehicles used may have contributed to an increased delivery of the test chemicals to target tissues.…”

Section: Discussionmentioning

confidence: 98%

Vehicle-Dependent Disposition Kinetics of Fluoranthene in Fisher-344 Rats

Harris

Hood

Ramesh

2008

IJERPH

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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 μg/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 μg/kg and 50 μg/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.

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Section: Discussionmentioning

confidence: 98%

Vehicle-Dependent Disposition Kinetics of Fluoranthene in Fisher-344 Rats

Harris

Hood

Ramesh

2008

IJERPH

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“…For example, differences in halocarbon toxicity using corn oil or an aqueous Emulphor vehicle have been investigated by several groups 7 – 11 with differences in toxicity due to the vehicle also being dependent on the type of toxicity – developmental, hepatotoxic and renal – as well as the dose. Similarly, aliphatic nitrile compounds have been investigated: Farooqui et al 12 showed that the toxicity of unsaturated aliphatic nitriles in Sprague-Dawley rats was reduced by using corn oil, safflower oil, mineral oil, olive oil or Tween-20 rather than saline. In contrast, Ghanayem et al 13 found that administration of methacrylonitrile in safflower oil was more toxic than in water.…”

Section: Introductionmentioning

confidence: 99%

Prediction of the effect of formulation on the toxicity of chemicals

et al. 2017

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“…The choice of a suitable dosing vehicle is an essential step in drug preclinical safety evaluation. Inappropriate selection of vehicle might influence the pharmacokinetics and toxicity of drugs (Farooqui et al , ; Kelava et al , ). Recently, the different vehicles from the discovery phase through early nonclinical safety assessment of drug development were summarized (Gad et al , ).…”

Section: Introductionmentioning

confidence: 99%

Corn oil as a vehicle in drug development exerts a dose‐dependent effect on gene expression profiles in rat thymus

Geng

Zhang

et al. 2012

J of Applied Toxicology

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The purpose of this study was to investigate the effects of corn oil (CO), which is widely used as a vehicle for water-insoluble agents in drug development, on the gene expression profiles in rat thymus with microarray technique. Female Wistar rats were administered daily with normal saline (NS) and CO 2, 5 and 10 ml kg⁻¹ per day for 14 days, respectively. Then, the thymus samples of rats were collected for microarray test and histopathology examination. CD4⁺ and CD8⁺ lymphocytes in peripheral blood were also numerated to assess the effects on lymphocyte subpopulations. The microarray data showed that the numbers of differentially expressed genes in the 2, 5 and 10 ml kg⁻¹ CO groups were 0, 40 and 458, respectively, compared with the NS control group. The altered genes were mainly associated with immune response, cellular response to organic cyclic substance and regulation of fatty acid β-oxidation. However, no abnormal changes in thymus weight, CD4⁺ and CD8⁺ lymphocytes counts and histopathological examination were observed in the three CO groups. These data showed that 10 ml kg⁻¹ CO, the usually recommended dosing volume as a vehicle in drug safety assessment, caused obvious dysregulated genes in rat thymus. Our study suggests that the appropriate dosing volume of CO gavage as a vehicle for water-insoluble agents in drug development should be 2 ml kg⁻¹ per day, if agent effects on thymus will be assessed in gene levels.

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Effect of dosing vehicle on the toxicity and metabolism of unsaturated aliphatic nitriles

Cited by 8 publications

References 19 publications

Vehicle-Dependent Disposition Kinetics of Fluoranthene in Fisher-344 Rats

Vehicle-Dependent Disposition Kinetics of Fluoranthene in Fisher-344 Rats

Prediction of the effect of formulation on the toxicity of chemicals

Corn oil as a vehicle in drug development exerts a dose‐dependent effect on gene expression profiles in rat thymus

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