Free chlorine reactions of angiotensin II receptor antagonists: Kinetics study, transformation products elucidation and in-silico ecotoxicity assessment

Abstract

Angiotensin II receptor antagonists (ARA II) are widely employed in the treatment of hypertension-related diseases. Because of their partial metabolization and limited biodegradability, these drugs have become ubiquitous pollutants in the aquatic environment, including surface water. This research evaluated the reactivity of the ARA II drugs: irbesartan (IRB), losartan (LOS) telmisartan (TEL) and valsartan (VAL) with free chlorine. Responses of parent compounds and their transformation products (TPs) were followed by liquid chromatography (LC) with quadrupole (Q) time-of-flight (TOF) mass spectrometry. Degradation experiments were carried out using ultrapure and river water samples, adjusted at different pHs and, in some cases, adding a small amount (ng mL−1 level) of bromide salts. Whilst TEL and VAL remained stable in presence of relatively high concentrations of free chlorine (10 mg L−1), IRB and LOS were removed according to a pseudo-first order kinetics model. Considering an initial chlorine concentration of 10 mg L−1, their half-lives varied between 6 and 734 min, depending mostly on the water pH. IRB reacted with free chlorine through hydroxylation processes, with and without molecular cleavage and re-arrangements in the imidazolone ring. Its TPs showed a lower in-silico predicted toxicity than the parent drug. In case of LOS, two major competitive degradation routes were identified. They involved replacement of the methanol group attached to the imidazole cycle by chlorine or bromine, and the cleavage of this cycle with removal of the chlorinated carbon and the nitrogen in alpha position. The TPs generated following the first route are predicted to be more toxic than LOS