ABSTRACT:In vitro biosynthesis using pooled human liver microsomes was applied to help identify in vivo metabolites of ketamine by liquid chromatography (LC)-tandem mass spectrometry. Microsomal synthesis produced dehydronorketamine, seven structural isomers of hydroxynorketamine, and at least five structural isomers of hydroxyketamine. To aid identification, stable isotopes of the metabolites were also produced from tetra-deuterated isotopes of ketamine or norketamine as substrates. Five metabolites (three hydroxynorketamine and two hydroxyketamine isomers) gave chromatographically resolved components with product ion spectra indicating the presence of a phenolic group, with phenolic metabolites being further substantiated by selective liquid-liquid extraction after adjustments to the pH. Two glucuronide conjugates of hydroxynorketamine were also identified. Analysis by LCcoupled ion cyclotron resonance mass spectrometry gave unique masses in accordance with the predicted elemental composition. The metabolites, including the phenols, were subsequently confirmed to be present in urine of subjects after oral ketamine administration, as facilitated by the addition of deuterated metabolites generated from the in vitro biosynthesis. To our knowledge, phenolic metabolites of ketamine, including an intact glucuronide conjugate, are here reported for the first time. The use of biologically synthesized deuterated material as an internal chromatographic and mass spectrometric marker is a viable approach to aid in the identification of metabolites. Metabolites that have particular diagnostic value can be selected as candidates for chemical synthesis of standards.

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Administration of ILE early after oral amitriptyline overdose resulted in worse survival and no improvement in haemodynamics. In addition, blood amitriptyline concentrations were higher in the ILE-treated group. This suggests that either drug absorption from the gastrointestinal-tract was facilitated or drug redistribution was retarded when ILE was given early after oral poisoning.

Electronic cigarettes (ECs) are thought to be less harmful than traditional combustible cigarettes and were originally intended to help smokers quit. Over the past two decades, they have especially gained popularity with the younger generation. To date, there are over 7000 unique e‐liquid flavours available and over 400 different e‐cigarette brands. The accuracy of nicotine strength labelling in e‐liquids was assessed in this work. Twenty‐three studies from around the world were chosen to assess the level and frequency of nicotine mislabelling in 545 e‐liquid products. Nicotine strengths were most commonly mislabelled by between 5% and 20%, with the majority testing lower than what the label indicated. Fifteen European e‐liquids that were assessed were labelled as 20 mg/ml or less, yet when tested, they contained more than 20 mg/ml of nicotine. One e‐liquid that was supposed to contain no nicotine in fact contained 23.91 mg/ml of nicotine. Furthermore, the difference between the medians of the available labelled and experimental nicotine concentrations was significant (p < 0.001, Wilcoxon signed rank test). Preliminary studies show that high nicotine levels delivered via aerosol increase the risk for nicotine poisoning and cause airway inflammation. Other EC ingredients, such as flavourings, contribute to EVALI and ‘popcorn lung’. There is evidence that certain flavourings, such as menthol, reinforce the effects of nicotine and modify drug absorption and metabolism. There is a global need for better quality control in EC products in order to make these safe for consumers.