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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.

Abstract：

:(-)-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-tetrahydrocannabinol-glucuronide ((-)-Δ-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-Δ-9-tetrahydrocannabinol-glucuronide ((-)-11-OH-Δ-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-Δ-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 (-)-Δ-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-Δ-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-Δ-9-THC is glucuronidated at either the phenolic or the alcoholic hydroxy group. A double glucuronidation was not observed. The alcoholic (-)-11-OH-Δ-9-THC-Glc was successfully chemically synthesized and identified the main alcoholic glucuronide in vitro and in vivo. (-)-11-OH-Δ-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.

journal_name

Int J Legal Med

journal_title

International journal of legal medicine

authors

Hassenberg C,Clausen F,Hoffmann G,Studer A,Schürenkamp J

doi

10.1007/s00414-020-02387-w

subject

Has Abstract

pub_date

2020-11-01 00:00:00

pages

2105-2119

issue

eissn

0937-9827

issn

1437-1596

pii

10.1007/s00414-020-02387-w

journal_volume

134

pub_type

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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.