title: The pH-dependent toxicity of basic pharmaceuticals in the green algae Scenedesmus vacuolatus can be explained with a toxicokinetic ion-trapping model.
abstract: Several previous studies revealed that pharmaceuticals with aliphatic amine function exhibit a higher toxicity toward algae than toward other aquatic organisms. Here we investigated the pH-dependent toxicity of the five basic pharmaceuticals fluoxetine, its metabolite norfluoxetine, propranolol, lidocaine, and trimipramine. For all of them, the toxicity increased with increasing pH when aqueous effect concentrations were considered. Since these pharmaceuticals contain a basic amine group that is protonated and thus positively charged at physiological pH and because algae are capable of biological homeostasis, i.e., pH inside the algal cell remains virtually independent of variable external pH, the speciation of aliphatic amines can be different inside the algal cell compared to the external medium. Therefore, we hypothesized that the high toxicity of aliphatic amines in algae is a toxicokinetic effect caused by speciation and not a toxicodynamic effect caused by a specific mode of toxic action. This hypothesis also implies that internal effect concentrations are independent on external pH. On this basis we developed a simple toxicokinetic model, which assumes that only the neutral molecule is bioavailable and can pass the plasma membrane. This assumption is likely to be valid at pH values down to two units below the acidity constant (pK(a)). For lower pH values a more complex model would have to be evoked that includes, an, albeit smaller, permeability of the charged species. For pH>pK(a)-2, we can safely assume that the outer membrane serves as insulator and that the charged species is formed inside the cell according to the pH in the cytoplasm. Thus this toxicokinetic model is an ion-trapping model. The input parameters of this model are the measured aqueous effect concentrations determined as a function of pH and the membrane-water partitioning, which was modelled by the liposome-water partition coefficients of the neutral and cationic species. They were deduced from experimentally determined liposome-water distribution ratios at various pH values measured with an equilibrium dialysis method. The modelled internal effect concentrations were independent of the external pH and effective membrane burdens were in the same range as for other baseline toxicants found in the literature for algae, daphnids and fish. These results confirm that the higher algal toxicity of pharmaceuticals with an aliphatic amine group can be explained by a toxicokinetic effect and that these pharmaceuticals do not exhibit a specific mode of action in algae but act as baseline toxicants.
authors.affiliation: Eawag, Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland.
authors.forename: Judith
authors.initials: J
authors.lastname: Neuwoehner
authors.forename: Beate I
authors.initials: BI
authors.lastname: Escher
mesh_terms: D000588:Amines / Q000737:chemistry / Q000633:toxicity*; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008012:Lidocaine / Q000633:toxicity; D008081:Liposomes / Q000737:chemistry; D008956:Models, Chemical; D011433:Propranolol / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D044444:Scenedesmus / Q000187:drug effects* / Q000378:metabolism*; D014299:Trimipramine / Q000633:toxicity; D014867:Water / Q000737:chemistry
chemical_list: D000588:Amines; D008081:Liposomes; D005473:Fluoxetine; D014867:Water; D014299:Trimipramine; D008012:Lidocaine; D011433:Propranolol; C036139:norfluoxetine