Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, in fathead minnows

John W. Nichols, Bowen Du, Jason P. Berninger, Kristin A. Connors, C. Kevin Chambliss, Russell J. Erickson, Alex D. Hoffman, Bryan W. Brooks

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

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 96h 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. 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.

Original languageEnglish (US)
Pages (from-to)1425-1435
Number of pages11
JournalEnvironmental Toxicology and Chemistry
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

Diphenhydramine
Cyprinidae
bioaccumulation
drug
Fish
Fishes
Acidification
Plasmas
plasma
Pharmaceutical Preparations
acidification
fish
chemical binding
drug development
pH effects
Acids
Water
Plasma Volume
acid
Blood

Keywords

  • Bioconcentration
  • Diphenhydramine
  • Fathead minnows
  • Ionizable organic chemicals
  • Pharmaceuticals

Cite this

Nichols, J. W., Du, B., Berninger, J. P., Connors, K. A., Chambliss, C. K., Erickson, R. J., ... Brooks, B. W. (2015). Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, in fathead minnows. Environmental Toxicology and Chemistry, 34(6), 1425-1435. https://doi.org/10.1002/etc.2948

Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, in fathead minnows. / Nichols, John W.; Du, Bowen; Berninger, Jason P.; Connors, Kristin A.; Chambliss, C. Kevin; Erickson, Russell J.; Hoffman, Alex D.; Brooks, Bryan W.

In: Environmental Toxicology and Chemistry, Vol. 34, No. 6, 01.06.2015, p. 1425-1435.

Research output: Contribution to journalArticle

Nichols, JW, Du, B, Berninger, JP, Connors, KA, Chambliss, CK, Erickson, RJ, Hoffman, AD & Brooks, BW 2015, 'Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, in fathead minnows', Environmental Toxicology and Chemistry, vol. 34, no. 6, pp. 1425-1435. https://doi.org/10.1002/etc.2948
Nichols, John W. ; Du, Bowen ; Berninger, Jason P. ; Connors, Kristin A. ; Chambliss, C. Kevin ; Erickson, Russell J. ; Hoffman, Alex D. ; Brooks, Bryan W. / Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, in fathead minnows. In: Environmental Toxicology and Chemistry. 2015 ; Vol. 34, No. 6. pp. 1425-1435.
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