Accounting for Differences in Plasma Protein Binding between Fish and Humans for Supporting Environmental Risk Assessment of Pharmaceuticals Using the Fish Plasma Model

The Fish Plasma Model (FPM) predicts steady-state concentrations of active pharmaceutical ingredients (APIs) in fish blood plasma based on partitioning from the surrounding (water) environment. Total plasma concentration is then compared to the human therapeutic concentration to indicate environmental risk, assuming that human pharmaceutical targets are conserved in fish. However, only the unbound fraction (fu) of API is available for pharmacological action and plasma protein binding, and the binding of APIs may differ between species. We quantify fu for 44 APIs with wide ranging physicochemical properties in three fish species: a salmonid, rainbow trout (Oncorhynchus mykiss) and two cyprinids, fathead minnow (Pimephales promelas), and koi carp (Cyprinus rubrofuscus), and draw comparisons with fu in humans. We examine interspecies differences in fu in relation to blood physicochemistry and protein and lipid composition. We show that anionic APIs often exhibit substantially (×10) higher fu in fish compared with humans, and this was most apparent in rainbow trout, despite this species possessing protein(s) orthologous to human serum albumin, a major binding protein for anionic APIs in humans. We recommend accounting for fu in fish versus humans and using rainbow trout as a conservative species in the FPM for modeling API availability and effects in fish.