Richter_2022_Drug.Test.Anal__

The synthetic cannabinoid receptor agonists (SCRAs) QMMSB (quinolin-8-yl 4-methyl-3-(morpholine-4-sulfonyl)benzoate) and QMiPSB (quinolin-8-yl 4-methyl-3-[(propan-2-yl)sulfamoyl]benzoate; also known as SGT-46) are based on the structure of QMPSB (quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate) that has been identified on seized plant material in 2011. In clinical toxicology, knowledge of the metabolic fate is important for their identification in biosamples. Therefore, the aim of this study was the identification of in vitro phase I and II metabolites of QMMSB and QMiPSB in pooled human liver S9 fraction (pHLS9) incubations for use as screening targets. In addition, the involvement of human monooxygenases and human carboxylesterases (hCES) was examined. Analyzes were performed by liquid chromatography coupled with high-resolution tandem mass spectrometry. Ester hydrolysis was found to be an important step in the phase I metabolism of both SCRAs, with the carboxylic acid product being found only in negative ionization mode. Monohydroxy and N-dealkyl metabolites of the ester hydrolysis products were detected as well as glucuronides. CYP2C8, CYP2C9, CYP3A4, and CYP3A5 were involved in hydroxylation. While enzymatic ester hydrolysis of QMiPSB was mainly catalyzed by hCES1 isoforms, non-enzymatic ester hydrolysis was also observed. The results suggest that ester hydrolysis products of QMMSB and QMiPSB and their glucuronides are suitable targets for toxicological screenings. The additional use of the negative ionization mode is recommended to increase detectability of analytes. Different CYP isozymes were involved in the metabolism, thus the probability of drug-drug interactions due to CYP inhibition can be assessed as low.