The effect of water pH on the uptake of acidic (ibuprofen) and basic (propranolol) drugs in a fish gill cell culture model

TY - JOUR

T1 - The effect of water pH on the uptake of acidic (ibuprofen) and basic (propranolol) drugs in a fish gill cell culture model

AU - Chang, Elisabeth Dohmann

AU - Town, Raewyn M.

AU - Owen, Stewart F.

AU - Hogstrand, Christer

AU - Bury, Nic R.

N1 - Funding Information: This work was conducted under funding awarded to N.R.B. and C.H.from the Biotechnology and Biological Sciences Research Council (BBSRC) CASE industrial scholarship scheme (reference BB/M014827/1) and the AstraZeneca Global SHE Research Programme. AstraZeneca is a biopharmaceutical company specializing in the discovery, development, manufacturing, and marketing of prescription medicines, including some products reported here. S.F.O. is an employee of AstraZeneca. R.M.T. conducted this research within the framework of the EXPOSOME center of excellence funded by Universiteit Antwerpen’s Bijzonder Onderzoeksfonds (BOF) and the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO) project G051117N (Unravelling the Nonspecific Mechanisms Underlying Nonpolar Narcotic Toxicity: Mitochondrial Effects). Publisher Copyright: © 2021 The Authors. Published by American Chemical Society.

PY - 2021/5/18

Y1 - 2021/5/18

N2 - Water pH is predicted to affect the uptake of ionisable pharmaceuticals in fish. The current study used an in vitro primary fish gill cell culture system (FIGCS) to assess the effect of pH-values in the range of 4.5 – 8.75 on the uptake rates of the base propranolol (pKa 9.42) and the acid ibuprofen (pKa 4.59). The rate limiting step in uptake was the diffusive supply flux of the unionised form from the water to the apical membrane, with subsequent rapid transfer across the epithelium. Computed uptake rate based on the unionised fraction best described the uptake of propranolol and ibuprofen over the range of pH values 5 – 8 and 6 – 8.75 values, respectively. For ibuprofen the computed uptake rate overestimated uptake below pH 6 where the unionised fraction increased from 4% at pH 6 to 55% at pH 4.5. As the unionised fraction increased the uptake rate plateaued suggesting a saturation of the transport process. For both drugs large variations in uptake occur with only small fluctuations in pH values. This occurs between pH 6 to 8 values, the pH range acceptable in regulatory test guidelines and seen in most of our freshwaters.

AB - Water pH is predicted to affect the uptake of ionisable pharmaceuticals in fish. The current study used an in vitro primary fish gill cell culture system (FIGCS) to assess the effect of pH-values in the range of 4.5 – 8.75 on the uptake rates of the base propranolol (pKa 9.42) and the acid ibuprofen (pKa 4.59). The rate limiting step in uptake was the diffusive supply flux of the unionised form from the water to the apical membrane, with subsequent rapid transfer across the epithelium. Computed uptake rate based on the unionised fraction best described the uptake of propranolol and ibuprofen over the range of pH values 5 – 8 and 6 – 8.75 values, respectively. For ibuprofen the computed uptake rate overestimated uptake below pH 6 where the unionised fraction increased from 4% at pH 6 to 55% at pH 4.5. As the unionised fraction increased the uptake rate plateaued suggesting a saturation of the transport process. For both drugs large variations in uptake occur with only small fluctuations in pH values. This occurs between pH 6 to 8 values, the pH range acceptable in regulatory test guidelines and seen in most of our freshwaters.

KW - Environmental pharmaceuticals

KW - Uptake

KW - Modelling

KW - Bioconcentration

KW - Accumulation

KW - Pollution

KW - Environmental Contamination

KW - pharmaceuticals

KW - APIs

KW - pH

KW - Gill

KW - Rainbow trout

UR - http://www.scopus.com/inward/record.url?scp=85103628586&partnerID=8YFLogxK

U2 - 10.1021/acs.est.0c06803

DO - 10.1021/acs.est.0c06803

M3 - Article

SN - 0013-936X

VL - 55

SP - 6848

EP - 6856

JO - Environmental Science and Technology

JF - Environmental Science and Technology

IS - 10

ER -