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THE ROLE OF MAMMALIAN DATA IN DETERMINING PHARMACEUTICAL RESPONSES IN AQUATIC SPECIES
Citation:
Kinter, L. B., D. B. Huggett, W H. Benson, K. Chipman, J. C. Cook, L. Gray, R. Meyerhoff, AND V. Trudeau. THE ROLE OF MAMMALIAN DATA IN DETERMINING PHARMACEUTICAL RESPONSES IN AQUATIC SPECIES. Presented at SETAC, Portland, OR, November 14 - 18, 2004.
Description:
Human pharmaceuticals are designed to be biologically active, and are extensively studies for physicalchemical, pharmacological, and toxicological properties. In those studies, efficacy and safety endpoints ED50s, LCSOs, NOAELs, LOAELs, etc.) are linked to plasma exposures (Cmax or ATJC) of a drug or metabolite in the relevant species. Pharmaceutical targets (e.g., receptorlenzyme subtypes) are well defined and many of these targets are evolutionally conserved across species, especially in fish, We propose a strategy utilizing this knowledge to assist in determining the need to conduct chronic ecotoxicity studies in fish or tadpoles (aquatic). In this model, mammalian plasma concentrations are compared to predicted aquatic plasma concentrations resulting in an exposure ratio (PER = mammal/aquatic) for a given drug. A functional equivalence ratio (FER) further describing aquatic/mammalian target relationships can be factored for a bioequivalence index (BE1 = PERIFER). A BE1 < 1 would indicate that chronic ecotoxicity testing in fish or tadpoles may be needed, with endpoints linked to the mammalian mechanism of action being considered.