A need exists to better understand the influence of pH on the uptake and accumulation of ionisable pharmaceuticals in fish. In the present study, fathead minnows were exposed to diphenhydramine (DPH; disassociation constant = 9.1) in water for up to 96 h at 3 nominal pH levels: 6.7, 7.7, and 8.7. In each case, an apparent steady state was reached by 24h, allowing for direct determination of the bioconcentration factor (BCF), blood-water partitioning (PBW,TOT ), and apparent volume of distribution (approximated from the whole-body-plasma concentration ratio). The BCFs and measured PBW,TOT values increased in a nonlinear manner with pH, whereas the volume of distribution remained constant, averaging 3.0 L/kg. The data were then simulated using a model that accounts for acidification of the gill surface caused by elimination of metabolically produced acid. The results showed good agreement between model simulations and measured data was obtained for all tests by assuming that plasma binding of ionised DPH is 16% that of the neutral form. A simpler model, which ignores elimination of metabolically produced acid, performed less well. These findings suggest that pH effects on accumulation of ionisable compounds in fish are best described using a model that accounts for acidification of the gill surface. Moreover, measured plasma binding and volume of distribution data for humans, determined during drug development, may have considerable value for predicting chemical binding behaviour in fish.
Authors: Nichols JW, Du B, Berninger JP, Connors KA, Chambliss CK, Erickson RJ, Hoffman AD, Brooks BW. ;Full Source: Environmental Toxicology & Chemistry. 2015 Jun;34(6):1425-35. doi: 10.1002/etc.2948. Epub 2015 Apr 28. ;