Ion-exchange removal of nonsteroidal anti-inflammatory drugs (NSAIDs) in synthetic urine can selectively remove pharmaceuticals with minimal coremoval of nutrients to enhance nutrient recovery efforts. However, the effect of endogenous metabolites in urine on ion-exchange removal, and the corresponding reduction in ecotoxicity potential of pharmaceuticals in treated urine entering the environment, is unknown. To assess treatment efficacy, this work paired predicted breakthrough curves determined by the homogeneous surface diffusion model to an in vitro bioassay to evaluate COX-1 inhibition. The presence of endogenous metabolites in urine significantly impacted pharmaceutical removal, by competing for ion-exchange sites on the resin and reducing the resin capacity for pharmaceuticals. This indicates ion-exchange would be ineffective at removing NSAIDs and other negatively charged compounds in urine. Due to hydrolysis of pharmaceutical metabolites back to the parent compound, treatment systems should be designed based on the ultimate pharmaceutical concentration in ureolyzed urine. Mass removal and COX-1 inhibition followed a nonlinear correlation and mixture toxicity followed the generalized concentration addition model. This work demonstrates the importance of evaluating removal of contaminants of emerging concern, such as pharmaceuticals, using a risk-based approach to ecotoxicity end points in conjunction with mass removal.