Metabolism of a new synthetic opioid tetrahydrofuranylfentanyl in fresh isolated human hepatocytes: Detection and confirmation of ring‐opened metabolites

The metabolism of a new synthetic opioid tetrahydrofuranylfentanyl (THF-fentanyl) was investigated using fresh human hepatocytes. Fourteen metabolites of THF-fentanyl, such as tetrahydrofuran ring-opened metabolites, desphenethylated metabolites, hydroxylated metabolites, and hydroxylated and methoxylated metabolites and their glucuronides, were detected in the culture medium of hepatocytes incubated with THF-fentanyl. Six metabolites, i.e. desphenethylated metabolite, 4'-hydroxy-THF-fentanyl, β-hydroxy-THF-fentanyl, 4'-hydroxy-3'-methoxy-THF-fentanyl, ring-opened alcohol metabolite, and ring-opened carboxylic acid metabolite, were identified via chemically synthesized authentic standards. A ring-opened alcohol metabolite and a ring-opened carboxylic acid metabolite are thought to be formed by reduction or oxidation of the intermediate aldehyde, which was formed by ring-opening of the metabolite hydroxylated at the carbon atom adjacent to the oxygen atom of the tetrahydrofuran ring. A ring-opened carboxylic acid metabolite was the main metabolite of THF-fentanyl based on the peak intensity.