Effect of Water pH on the Uptake of Acidic (Ibuprofen) and Basic (Propranolol) Drugs in a Fish Gill Cell Culture Model

Elisabeth Dohmann Chang,Raewyn M Town,Stewart F Owen,Christer Hogstrand,Nic R Bury

doi:10.1021/acs.est.0c06803

Abstract

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

Highlights

There is a paucity of data for drug ADME for fish,[24] with absorption and metabolism processes representing the largest factors of uncertainty in current accumulation models.[2,25,26]
Disturbances in the pH of the ambient water have a marked effect on acid−base balance in fish; for example, the expired water from across the gills is acidified when the fish are exposed to high external pH (9.91) and alkalinized during low external pH (3.88) exposure.[61]
The gills play a major role in internal pH regulation via acid−base equivalent exchange[62] that may affect external water pH and the species of ionizable compounds

Summary

INTRODUCTION

Human and veterinary pharmaceuticals are biologically active compounds with concentrations in global freshwater environments being measured at the pg−μg/L range[1] and accumulation in biota being observed.[2,3] This raises concerns about the effect these compounds may have on aquatic organisms because many human drug targets are evolutionarily conserved in fish and aquatic invertebrates.[4−7] Adverse effects have been observed for a number of drugs when internal concentrations in fish exceed the human therapeutic plasma concentrations,[8] for example, ethinyl oestradiol,[9] fluoxetine,[10,11] glucocorticoids,[12−15] ibuprofen,[16] propranolol,[17] and salbutamol.[18]. The FIGCS has been used to measure drug uptake from the water across the epithelium[51] and to develop a model based on chemical descriptors to describe drug uptake.[52] In the latter study, water chemistry was kept constant with a pH value of 7.6 and the uptake of 10 drugs, including acidic, basic, and neutral drugs monitored, and the model that best-described the uptake showed a positive correlation to drug solubility (Log S) and a negative correlation to pKa.[52] The current study uses the same in vitro model but focuses on the basic drug propranolol (pKa 9.42) and acid ibuprofen (pKa 4.59) uptake in the pH range of 4.5 to 8.75, with the aim to assess how drug ionization influences gill uptake and the hypothesis that the unionized fraction is more readily bioavailable

MATERIALS AND METHODS

RESULTS AND DISCUSSION

ENVIRONMENTAL IMPLICATIONS

■ ACKNOWLEDGMENTS

■ REFERENCES