期刊
INTERNATIONAL JOURNAL OF LEGAL MEDICINE
卷 134, 期 6, 页码 2105-2119出版社
SPRINGER
DOI: 10.1007/s00414-020-02387-w
关键词
Cannabis; (-)-Delta-9-THC; (-)-11-OH-Delta-9-THC; Phase II metabolism; Synthesis of alcoholic (-)-11-OH-Delta-9-THC-glucuronide
资金
- Projekt DEAL
- Westphalian Wilhelms University, Munster
(-)-Delta-9-tetrahydrocannabinol ((-)-Delta-9-THC) is the main psychoactive constituent in cannabis. During phase I metabolism, it is metabolized to (-)-11-hydroxy-Delta-9-tetrahydrocannabinol ((-)-11-OH-Delta-9-THC), which is psychoactive, and to (-)-11-nor-9-carboxy-Delta-9-tetrahydrocannabinol ((-)-Delta-9-THC-COOH), which is psychoinactive. It is glucuronidated during phase II metabolism. The biotransformation of (-)-Delta-9-tetrahydrocannabinol-glucuronide ((-)-Delta-9-THC-Glc) and (-)-11-nor-9-carboxy-Delta-9-tetrahydrocannabinol-glucuronide ((-)-Delta-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-Delta-9-tetrahydrocannabinol-glucuronide ((-)-11-OH-Delta-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-Delta-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 (-)-Delta-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-Delta-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-Delta-9-THC is glucuronidated at either the phenolic or the alcoholic hydroxy group. A double glucuronidation was not observed. The alcoholic (-)-11-OH-Delta-9-THC-Glc was successfully chemically synthesized and identified the main alcoholic glucuronide in vitro and in vivo. (-)-11-OH-Delta-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.
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