Abstract
Alterations in ivermectin (IVM, 22,23-dihydro avermectin B1a+22,23-dihydro avermectin B1b) toxicokinetics following P-glycoprotein (P-gp) induction by clotrimazole (CTZ) were examined in rainbow trout (Oncorhynchus mykiss) to assess the potential importance of P-gp activity levels in xenobiotic distribution and kinetics in fish. Control and fish pretreated with CTZ (30 µmol/kg) were administered 175 µg/kg 3H-IVM into the caudal vasculature. At various time points (0.25, 0.5, 1, 3, 24, 48, 96, and 168 h) following injection, tissues (blood, liver, kidney, gill, intestines, brain [5 regions], eye, gonad and fat) were removed analyzed for IVM-derived radioactivity. IVM concentration declined in blood, liver, kidney and gill, and concentrations in other tissues remained constant over the sampling period. The highest measured concentrations were found in kidney, followed by liver, with the lowest values found in brain, eye and gonad. The highest % of the administered dose was found in the liver and kidney in the immediate hours post-administration, and in the intestines and fat at 24 h post-administration. P-gp induction by CTZ did not alter IVM distribution or any calculated toxicokinetic parameter (AUC, mean residence time, T1/2, clearance rate, volume of distribution), suggesting that P-gp induction may be limited or that P-gp plays a lesser role in xenobiotic kinetics in fish compared to mammals.
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Acknowledgements
The authors are grateful to Mr. Ian Bercovitz for providing statistical consultation and useful advice in data analyses, and to Mike Xu, Geoffrey Su, John Camino, Ankita Ansal, Jolena Ye, Zahra Effati Sabet and Ashley Ives for assisting in experiment preparation (labelling and solution preparation), fish dissection and sample collection.
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Research funding was provided by an NSERC Discovery Grant to CJK. VCA was supported by Science Without Borders (CAPES – Proc. No. 1346-13-7, Brazil).
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Cavicchioli Azevedo, V., Johnston, C.U. & Kennedy, C.J. Ivermectin Toxicokinetics in Rainbow Trout (Oncorhynchus mykiss) following P-glycoprotein Induction. Arch Environ Contam Toxicol 86, 58–72 (2024). https://doi.org/10.1007/s00244-023-01045-7
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DOI: https://doi.org/10.1007/s00244-023-01045-7