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Recent species-extrapolation approaches to the prediction of the potential effects of pharmaceuticals present in the environment on wild fish are based on the assumption that pharmacokinetics and metabolism in humans and fish are comparable. To test this hypothesis, we exposed fathead minnows to the opiate pro-drug tramadol and examined uptake from the water into the blood and brain and the metabolism of the drug into its main metabolites. We found that plasma concentrations could be predicted reasonably accurately based on the lipophilicity of the drug once the pH of the water was taken into account. The concentrations of the drug and its main metabolites were higher in the brain than in the plasma, and the observed brain and plasma concentration ratios were within the range of values reported in mammalian species. This fish species was able to metabolize the pro-drug tramadol into the highly active metabolite O-desmethyl tramadol and the inactive metabolite N-desmethyl tramadol in a similar manner to that of mammals. However, we found that concentration ratios of O-desmethyl tramadol to tramadol were lower in the fish than values in most humans administered the drug. Our pharmacokinetic data of tramadol in fish help bridge the gap between widely available mammalian pharmacological data and potential effects on aquatic organisms and highlight the importance of understanding drug uptake and metabolism in fish to enable the full implementation of predictive toxicology approaches.
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Background: Tetrazole derivatives such as 1-substituted dinitrobenzyl tetrazoles and their oxa and selanyl analogs have previously been studied against drug-susceptible and multidrugresistant mycobacteria. In addition, other tetrazole derivatives have been shown to inhibit CTX-M class A μ-lactamases. Objective: To study the antibacterial activity of 5-substituted aryl 1H-tetrazole derivatives. Methods: The antibacterial activity of several known 5-substituted aryl 1H-tetrazole derivatives was evaluated against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The activity was assessed by determining the minimum inhibitory concentration of these tetrazole derivatives and comparing them to the known antibiotics amoxicillin, trimethoprim and sulfamethoxazole. Results: Some derivatives showed significant antibacterial activity with the most active derivatives exhibiting a minimum inhibitory concentration (MIC) of 125-250 μg/mL against Staphylococcus aureus and Escherichia coli. Using some of these tetrazole compounds in combination with trimethoprim led to a synergistic effect that gave MIC values ranging from 0.24-1.95 μg/mL against Escherichia coli and 3.91-31.3 μg/mL against Staphylococcus aureus. The tetrazole derivatives were prepared in an isopropanol/water mixture using microwave heating at 160 °C for 1h. The cycloaddition between organonitriles and sodium azide was catalyzed by indium chloride. Conclusion: This study shows a significant synergistic effect between the tetrazole compounds tested and trimethoprim which could be used to potentially develop new antibacterial agents. © 2017 Bentham Science Publishers.