Uptake and Metabolism of Human Pharmaceuticals by Fish - A Case Study with the Opioid Analgesic Tramadol.

This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Environmental science & technology, copyright © American Chemical Society after peer review. To access the final edited and published work see https://doi.org/10.1021/acs.est.7b03441Recent species-extrapolation approaches to predict 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 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/plasma concentration ratios were within the range of values reported in mammalian species. This fish species was able to metabolise the pro-drug tramadol into the highly active metabolite O-desmethyl tramadol and the inactive metabolite N-desmethyl tramadol in a similar manner to 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.We would like to thank members of the Ecotoxicology Research Group, Brunel University London, particularly J. Walker, N. Brodigan, and A. Ferreira for fish husbandry, and T. Thrupp, E. Lawton, and A. Baynes for fish sampling. The research at Brunel University London was internally funded by the university. This study was also supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) to a project on Joint Usage/Research Center– Leading Academia in Marine and Environment Pollution Research (LaMer), and Research Fellowships from the Japan Society for the Promotion of Science (JSPS) for Young Scientists in Japan (PD) provided to R. Tanoue (26·2800), Grants in Bid (KAKENHI) for Scientific Research (A) (25257403), Scientific Research (A) (16H01784). This study was also funded by the Sasakawa Scientific Research Grant from The Japan Science Society