Metabolic Profile of Etomidate and Its Three Analogs in Zebrafish, Human Liver Microsomes, Human Urine and Hair Samples Using UHPLC‐Q Exactive Orbitrap‐HRMS

Etomidate is a short-acting non-barbiturate imidazole used as an intravenous anesthetic agent in humans, while metomidate and propoxate are common anesthetic drug for fishes. Today, etomidate, and its analogs, including isopropoxate, are increasingly abused, leading to many public malignant events. The goal of this work was to use liquid chromatography-high resolution mass spectrometry (LC-HRMS) to study the in vivo and in vitro metabolism of etomidate and its analogs in zebrafish, human liver microsomes (HLMs), human urine and hair samples. Eight metabolites of metomidate, 11 metabolites of etomidate, six metabolites of propoxate, and 10 metabolites of isopropoxate were detected in our study. The main metabolic pathways included hydroxylation, dealkylation, dehydrogenation, and glucuronidation. Etomidate acid and metomidate were detected in samples after metabolism of all four substances. Our results support the use of the monohydroxylated metabolites as metabolic biomarkers for etomidate and its analogs. Among the tested human samples, 38 samples showed one type of our targeted substances, and 20 samples showed two or more drugs. Thus, polydrug use in etomidate and its analogs was a phenomenon worth noting. This study is the first to identify target metabolic compounds for monitoring the abuse of etomidate and its analogs in human, and to provide insights into the in vivo and in vitro biotransformation of them.