UC Riverside

Pharmaceuticals are contaminants of emerging concern because they are designed to elicit biological responses at low doses. Antidepressants and β-blockers, which are largely chiral compounds, are the most frequently and abundantly detected pharmaceuticals in the environment. Enantiomers of chiral pharmaceuticals behave differently in biological systems. However, most studies on occurrence, fate and toxicity overlook chirality. There is an inadequate understanding of mechanisms of stereoselectivity in adsorption, biodegradation and environmental toxicity of chiral pharmaceuticals.

We determined the mechanism of chiral separation of atenolol and fluoxetine in a macrocyclic glycopeptide-based column using different types of liophilic ions as mobile phase additives. Liophilic ions affected the retention factor, and the magnitude of the effect depended on their hydrophobicity: CH3COO− > HCOO− > NO3−. The enantioresolution decreased when the concentration of liophilic ions was increased from 4 to 20 mM suggesting analyte retention was predominantly due to dynamic ion exchange.

We systematically studied the effect of chirality on the adsorption of β-blockers to wastewater sludge. The (S)-enantiomers of acebutolol and metoprolol had Kd values approximately twice that of the (R)-enantiomers, that is, 109 ± 11 and 57 ± 8 L/kg compared to 52 ± 13 and 22 ± 8 L/kg, respectively. The relatively more hydrophobic compounds, pindolol and propranolol did not exhibit stereoselectivity toward adsorption. Our results suggest that ionic interactions and hydrogen bonding contribute significantly to stereoselectivity in adsorption of the tested compounds.

We comprehensively investigated stereoselectivity in the biodegradation of β-blockers in wastewater treatment plants. The degradation of 5 β-blockers in wastewater microcosms was also investigated. We observed S-enrichment in the degradation of metoprolol, pindolol and propranolol with the EF value changing from 0.5 to 0.30 ± 0.01, 0.37 ± 0.0 and 0.32 ± 0.05, respectively. The results from the wastewater microcosm parameterized the Rayleigh equation offering valuable quantitative assessment data that can be used to improve the accuracy of the environmental risk assessment of chiral pharmaceuticals.

The applicability of the read-across hypothesis in predicting stereoselective toxicity of 11 pharmaceuticals to aquatic organisms was performed using the Fish Plasma Model. We found metoprolol had high risk because its effect ratio, ER (ratio of human therapeutic plasma concentration to fish plasma concentration at steady state) was less than 1.0, whereas propranolol, salbutamol, fluoxetine and venlafaxine had medium risk (1.0 < ER < 30). Stereoselectivity was observed in all compounds except atenolol and pindolol. We showed that the read-across hypothesis is a useful tool for predicting stereoselective toxicity of chiral pharmaceuticals.

The results suggest stereoselectivity is prevalent in wastewater and the environment, and that pharmacological data can be used in predicting enantiomeric differences in the aquatic toxicity of chiral pharmaceuticals.