Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, in fathead minnows.
A need exists to better understand the influence of pH on the uptake and accumulation of ionizable 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 24 h, 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. Good agreement between model simulations and measured data was obtained for all tests by assuming that plasma binding of ionized 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 ionizable 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 behavior in fish.
Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota, USA.
John W
JW
Nichols
Department of Environmental Science, Baylor University, Waco, Texas, USA.|Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, Texas, USA.|The Institute of Ecological, Earth and Environmental Sciences, Baylor University, Waco, Texas, USA.
Bowen
B
Du
Department of Environmental Science, Baylor University, Waco, Texas, USA.|Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, Texas, USA.|Institute of Biomedical Studies, Baylor University, Waco, Texas, USA.
Jason P
JP
Berninger
Department of Environmental Science, Baylor University, Waco, Texas, USA.|Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, Texas, USA.|Institute of Biomedical Studies, Baylor University, Waco, Texas, USA.
Kristin A
KA
Connors
Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, Texas, USA.|The Institute of Ecological, Earth and Environmental Sciences, Baylor University, Waco, Texas, USA.|Department of Chemistry and Biochemistry, Baylor University, Waco, Texas, USA.
C Kevin
CK
Chambliss
Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota, USA.
Russell J
RJ
Erickson
Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota, USA.
Alex D
AD
Hoffman
Department of Environmental Science, Baylor University, Waco, Texas, USA.|Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, Texas, USA.|The Institute of Ecological, Earth and Environmental Sciences, Baylor University, Waco, Texas, USA.|Institute of Biomedical Studies, Baylor University, Waco, Texas, USA.
Bryan W
BW
Brooks
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003530:Cyprinidae / Q000378:metabolism*; D004155:Diphenhydramine / Q000097:blood / Q000737:chemistry / Q000633:toxicity*; D005880:Gills / Q000187:drug effects* / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000097:blood / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008954:Models, Biological; D053719:Tandem Mass Spectrometry; D014867:Water / Q000737:chemistry; D014874:Water Pollutants, Chemical / Q000097:blood / Q000737:chemistry / Q000633:toxicity*
D006634:Histamine H1 Antagonists; D014874:Water Pollutants, Chemical; D014867:Water; D004155:Diphenhydramine
Bioconcentration; Diphenhydramine; Fathead minnows; Ionizable organic chemicals; Pharmaceuticals