pH‐Dependent Uptake and Sublethal Effects of Antihistamines in Zebrafish (Danio rerio) Embryos
- 19 February 2019
- journal article
- research article
- Published by Wiley in Environmental Toxicology and Chemistry
- Vol. 38 (5), 1012-1022
- https://doi.org/10.1002/etc.4395
Abstract
Reported off‐target effects of antihistamines in humans draw interest in ecotoxicity testing of first‐ and second‐generation antihistamines, the latter of which have fewer reported side effects in humans. As antihistamines are ionizable compounds, the pH influences uptake and toxicity and thus is highly relevant when conducting toxicity experiments. Zebrafish embryo toxicity tests were performed with the 3 first‐generation antihistamines ketotifen, doxylamine and dimethindene and the 2 second‐generation antihistamines cetirizine and levocabastine at pH 5.5, 7.0 and 8.0. We detected effects on survival, phenotype, swimming activity and heart rate for 4 antihistamines with exception of levocabastine, which did not show any lethal or sublethal effects. When compared to lethal concentrations, effect concentrations neither of phenotype malformation, nor of swimming activity or heart rate, deviated by more than a factor of 10 from lethal concentrations, indicating that all sublethal effects were fairly non‐specific. First‐generation antihistamines are weak bases and showed decreasing external effect concentrations with increasing neutral fraction, accompanied by increased uptake in the fish embryo. As a result, internal effect concentrations were independent from external pH. The pH‐dependent toxicity originates from speciation‐dependent uptake, with neutral species taken up in higher amounts than the corresponding ionic species. Cetirizine, which shifts from zwitterionic to anionic state in the measured pH‐range, did not show any pH‐dependent uptake or toxicity. This article is protected by copyright. All rights reservedKeywords
Funding Information
- Innovative Medicines Initiative (115735)
This publication has 51 references indexed in Scilit:
- Pharmacology of antihistaminesIndian Journal of Dermatology, 2013
- The significance of acid/base properties in drug discoveryChemical Society Reviews, 2012
- The pH-dependent toxicity of basic pharmaceuticals in the green algae Scenedesmus vacuolatus can be explained with a toxicokinetic ion-trapping modelAquatic Toxicology, 2011
- The effect of pH on the uptake and toxicity of the bivalent weak base chloroquine tested on Salix viminalis and Daphnia magnaEnvironmental Toxicology and Chemistry, 2010
- Contamination of surface, ground, and drinking water from pharmaceutical productionEnvironmental Toxicology and Chemistry, 2009
- Development of zebrafish swimbladder: The requirement of Hedgehog signaling in specification and organization of the three tissue layersDevelopmental Biology, 2009
- Dose-dependent effects of chemical immobilization on the heart rate of embryonic zebrafishLab Animal, 2006
- Antimuscarinic actions of antihistamines on the heartJournal of Biomedical Science, 2006
- Peer Reviewed: Internal Exposure: Linking Bioavailability to EffectsEnvironmental Science & Technology, 2004
- Zebrafish M2 muscarinic acetylcholine receptor: cloning, pharmacological characterization, expression patterns and roles in embryonic bradycardiaBritish Journal of Pharmacology, 2002