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Investigation of phase II metabolism of 11-hydroxy-?-9-tetrahydrocannabinol and metabolite verification by chemical synthesis of 11-hydroxy-?-9-tetrahydrocannabinol-glucuronide.

ABSTRACT: (-)-?-9-tetrahydrocannabinol ((-)-?-9-THC) is the main psychoactive constituent in cannabis. During phase I metabolism, it is metabolized to (-)-11-hydroxy-?-9-tetrahydrocannabinol ((-)-11-OH-?-9-THC), which is psychoactive, and to (-)-11-nor-9-carboxy-?-9-tetrahydrocannabinol ((-)-?-9-THC-COOH), which is psychoinactive. It is glucuronidated during phase II metabolism. The biotransformation of (-)-?-9-tetrahydrocannabinol-glucuronide ((-)-?-9-THC-Glc) and (-)-11-nor-9-carboxy-?-9-tetrahydrocannabinol-glucuronide ((-)-?-9-THC-COOH-Glc) is well understood, which is mainly due to the availability of commercial reference standards. Since such a standardized reference is not yet available for (-)-11-hydroxy-?-9-tetrahydrocannabinol-glucuronide ((-)-11-OH-?-9-THC-Glc), its biotransformation is harder to study and the nature of the glucuronide bonding-alcoholic and/or phenolic-remains unclear. Consequently, the aim of this study was to investigate the biotransformation of (-)-11-OH-?-9-THC-Glc in vitro as well as in vivo and to identify the glucuronide by chemically synthesis of a reference standard. For in vitro analysis, pooled human S9 liver fraction was incubated with (-)-?-9-THC. Resulting metabolites were detected by high-performance liquid chromatography system coupled to a high-resolution mass spectrometer (HPLC-HRMS) with heated electrospray ionization (HESI) in positive and negative full scan mode. Five different chromatographic peaks of OH-?-9-THC-Glc have been detected in HESI positive and negative mode, respectively. The experiment set up according to Wen et al. indicates the two main metabolites being an alcoholic and a phenolic glucuronide metabolite. In vivo analysis of urine (n?=?10) and serum (n?=?10) samples from cannabis users confirmed these two main metabolites. Thus, OH-?-9-THC is glucuronidated at either the phenolic or the alcoholic hydroxy group. A double glucuronidation was not observed. The alcoholic (-)-11-OH-?-9-THC-Glc was successfully chemically synthesized and identified the main alcoholic glucuronide in vitro and in vivo. (-)-11-OH-?-9-THC-Glc is the first reference standard for direct identification and quantification. This enables future research to answer the question whether phenolic or alcoholic glucuronidation forms the predominant way of metabolism.

SUBMITTER: Hassenberg C

PROVIDER: S-EPMC7578173 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Investigation of phase II metabolism of 11-hydroxy-Δ-9-tetrahydrocannabinol and metabolite verification by chemical synthesis of 11-hydroxy-Δ-9-tetrahydrocannabinol-glucuronide.

Hassenberg Christoph C Clausen Florian F Hoffmann Grete G Studer Armido A Schürenkamp Jennifer J

International journal of legal medicine 20200817 6

(-)-Δ-9-tetrahydrocannabinol ((-)-Δ-9-THC) is the main psychoactive constituent in cannabis. During phase I metabolism, it is metabolized to (-)-11-hydroxy-Δ-9-tetrahydrocannabinol ((-)-11-OH-Δ-9-THC), which is psychoactive, and to (-)-11-nor-9-carboxy-Δ-9-tetrahydrocannabinol ((-)-Δ-9-THC-COOH), which is psychoinactive. It is glucuronidated during phase II metabolism. The biotransformation of (-)-Δ-9-tetrahydrocannabinol-glucuronide ((-)-Δ-9-THC-Glc) and (-)-11-nor-9-carboxy-Δ-9-tetrahydrocanna ...[more]

PMID: 32808050

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Project description:Polydrug use is common, and might occur because certain individuals experience positive effects from several different drugs during early stages of use. This study examined individual differences in subjective responses to single oral doses of d-amphetamine, alcohol, and delta-9-tetrahydrocannabinol (THC) in healthy social drinkers. Each of these drugs produces feelings of well-being in at least some individuals, and we hypothesized that subjective responses to these drugs would be positively correlated. We also examined participants' drug responses in relation to personality traits associated with drug use. In this initial, exploratory study, 24 healthy, light drug users (12 male, 12 female), aged 21-31 years, participated in a fully within-subject, randomized, counterbalanced design with six 5.5-hour sessions in which they received d-amphetamine (20mg), alcohol (0.8 g/kg), or THC (7.5 mg), each paired with a placebo session. Participants rated the drugs' effects on both global measures (e.g. feeling a drug effect at all) and drug-specific measures. In general, participants' responses to the three drugs were unrelated. Unexpectedly, "wanting more" alcohol was inversely correlated with "wanting more" THC. Additionally, in women, but not in men, "disliking" alcohol was negatively correlated with "disliking" THC. Positive alcohol and amphetamine responses were related, but only in individuals who experienced a stimulant effect of alcohol. Finally, high trait constraint (or lack of impulsivity) was associated with lower reports of liking alcohol. No personality traits predicted responses across multiple drug types. Generally, these findings do not support the idea that certain individuals experience greater positive effects across multiple drug classes, but instead provide some evidence for a "drug of choice" model, in which individuals respond positively to certain classes of drugs that share similar subjective effects, and dislike other types of drugs.

Dataset Information

Investigation of phase II metabolism of 11-hydroxy-?-9-tetrahydrocannabinol and metabolite verification by chemical synthesis of 11-hydroxy-?-9-tetrahydrocannabinol-glucuronide.

Publications

Investigation of phase II metabolism of 11-hydroxy-Δ-9-tetrahydrocannabinol and metabolite verification by chemical synthesis of 11-hydroxy-Δ-9-tetrahydrocannabinol-glucuronide.

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