TY - JOUR
T1 - Uptake and Metabolism of Human Pharmaceuticals by Fish
T2 - A Case Study with the Opioid Analgesic Tramadol
AU - Tanoue, Rumi
AU - Margiotta-Casaluci, Luigi
AU - Huerta, Belinda
AU - Runnalls, Tamsin J.
AU - Nomiyama, Kei
AU - Kunisue, Tatsuya
AU - Tanabe, Shinsuke
AU - Sumpter, John P.
N1 - Funding Information:
Test Fish. Adult fathead minnows (P. promelas), approximately 7 months old, 2.6 ± 0.53 g average weight, and 5.4 ± 0.30 cm average length, were supplied from breeding stocks maintained at Brunel University London, UK. A total of 10 days before the beginning of chemical dosing, sexually mature males were transferred into the flow-through systems for acclimation to the test conditions. Fish were fed three times per day, once with adult brine shrimp (Tropical Marine Centre, Gamma irradiated) and twice with flake food (King British Tropical flake food), throughout the experiment. This study was carried out under Project and Personnel Licenses granted by the UK Home Office, which follows the United Kingdom Animals (Scientific Procedures) Act 1986, and the European Animal Directive 2010/63/EU.
Funding Information:
We 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.T. (26·2800), Grants-in-Aid (KAKENHI) for Scientific Research (A) (25257403) and Scientific Research (A) (16H01784). This study was also funded by the Sasakawa Scientific Research Grant from The Japan Science Society.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/11/7
Y1 - 2017/11/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047772812&partnerID=8YFLogxK
U2 - 10.1021/acs.est.7b03441
DO - 10.1021/acs.est.7b03441
M3 - Article
C2 - 28977743
AN - SCOPUS:85047772812
SN - 0013-936X
VL - 51
SP - 12825
EP - 12835
JO - Environmental Science and Technology
JF - Environmental Science and Technology
IS - 21
ER -