Expanding environmental monitoring of psychotropic drugs by incorporating human metabolites through tandem solid-phase extraction.

The occurrence of psychotropic drugs in aquatic environments has attracted increasing attention worldwide because of their various ecological toxicities. However, information on their human metabolites remains limited, although some metabolites might retain biological activity and even exhibit stronger biological effects than their parent pharmaceuticals. To accurately characterize the environmental distribution of psychotropic drugs and their human metabolites in aquatic environments, it is necessary to develop analytical methods for their simultaneous determination in environmental waters. In this study, 69 psychotropic drugs and metabolites were selected as target analytes to systematically evaluate their recovery behaviors across different SPE sorbents and develop a reliable extraction method for simultaneous determination of parent compounds and metabolites. The results indicated that the recoveries of 16, 30, and 34 target analytes ranged from 70% to 120% for HLB, MCX, and WAX, respectively. Among them, six hydrophobic and protonatable metabolites exhibited low recoveries on MCX. These low recoveries were associated with metabolic transformation type and modification site, particularly N-demethylation, hydroxylation, and epoxidation, indicating that SPE sorbents may introduce selective recovery bias in metabolite analysis. In addition, HLB and WAX also showed selective recovery differences for specific metabolites, mainly related to insufficient retention of highly polar or structurally modified metabolites. Based on the complementary retention characteristics of different sorbents, an HLB-MCX tandem solid-phase extraction strategy was developed to improve the recovery of structurally diverse psychotropic drugs and their metabolites. It was further applied to determine the psychotropic drugs and metabolites in both wastewater and surface water. Thirteen and eight metabolites were detected in wastewater and surface water, respectively, with concentrations ranging from <LOQ to 214 ng/L and <LOQ to 195 ng/L. These results highlight the importance of incorporating human metabolites into psychotropic drug monitoring and further evaluating their potential environmental risks.