Detection of ADB-BUTINACA Metabolites in Human Urine, Blood, Kidney and Liver.

The N-butyl indazole derivative, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-butyl-1H-indazole-3-carboxamide (ADB-BUTINACA or ADB-BINACA), currently a drug of abuse in Russia, is reported to have a cannabinoid receptor potency and efficacy almost three times higher than JWH-018. ADB-BUTINACA was detected in blood from patients with suspected drug intoxications, as well as in blood, kidney and liver samples collected during postmortem investigations. Using liquid chromatography-time-of-flight-mass spectrometry, a number of ADB-BUTINACA metabolites were tentatively identified in urine samples. These include products of mono- and dihydroxylation, hydroxylation of the N-butyl side chain and dehydrogenation, formation of a dihydrodiol, hydrolysis of the terminal amide group, N-dealkylation of the indazole and a combination of these reactions. The dihydrodiol was found to be the predominant metabolite, with its chromatographic peak area exceeding those of other metabolites by almost an order of magnitude. For the routine analysis of blood, liver and kidney samples, the dihydrodiol and monohydroxylated metabolites along with the parent compound are recommended as target analytes. The same metabolites in free and glucuronidated forms are also recommended for analytical confirmation in urine samples.

Tentative identification of the metabolites of (1-(cyclohexylmethyl)-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone, and the product of its thermal degradation, by in vitro and in vivo methods.

Synthetic cannabinoids (SCs), mimicking the psychoactive effects of cannabis, consist of a vast array of structurally diverse compounds. A novel compound belonging to the SC family, (1-(cyclohexylmethyl)-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone (named TMCP-CHM in this article) contains a cyclopropane ring that isomerizes during the smoking process, resulting in a ring-opened thermal degradant with a terminal double bond in its structure. Metabolites of TMCP-CHM were tentatively identified in vitro (after incubation of the parent substance with S9 pooled human liver fraction) and in vivo (rat experimental model) studies by accurate-mass liquid chromatography-tandem mass spectrometry (LC-MS/MS). For the identification of the degradant metabolites, and to study biotransformation of parent substance in the human, urine and hair samples from patients, who had ingested the compound and were subsequently admitted to hospital with drug intoxications, were analyzed. Products of mono-, di-, trihydroxylation, carboxylation, and carboxylation combined with hydroxylation of TMCP-CHM and its degradant were detected in human urine. Metabolism of the degradant included addition of water to the terminal double bond followed by dehydration and formation of a cyclic metabolite. Degradant metabolites prevailed in comparison with metabolites of the parent substance in each metabolite group examined, except carboxylation. N-Dealkylated metabolites found in human urine originated only from the degradant. Most of the hydroxy metabolites were detected in human urine in both the free form and as glucuronides. The detection of monohydroxylated (M1.1-M1.3, M/A1.10) and carboxylated/hydroxylated (M4.2, M/A4.3) metabolites of TMCP-CHM and the hydrated form of the monohydroxylated metabolite of the degradant was found to be convenient for routine analysis.