Schirmer Willi, Schürch Stefan, Weinmann Wolfgang
Institute of Forensic Medicine, Forensic Toxicology and Chemistry, University of Bern, Bern, Switzerland.
Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland.
Drug Test Anal. 2025 Feb 21. doi: 10.1002/dta.3871.
Hexahydrocannabiphorol (HHCP) is an emerging semisynthetic cannabinoid, which has been known since 1942 from research of tetrahydrocannabinol (THC) analogs and homologs. After the ban of hexahydrocannabinol (HHC) in many European Countries HHCP emerged as a replacement among other similar compounds. First countries already placed HHCP under their narcotic substance law. The aim of this research was to identify human Phase I and II metabolites in urine after oral HHCP consumption. Enzymatic immunoassays of urine samples were tested negative for cannabinoids after a single oral consumption of 4-mg HHCP from a Δ-THC abstinent volunteer. The HHCP sample consumed in the self-experiment was purchased from an online store and analyzed beforehand using GC-MS. LC-HR-MS/MS and GC-MS after derivatization were used for the identification of metabolites. Hydroxylated metabolites were found with hydroxylation on the side chain or on the alicyclic part of the molecule. Bishydroxylated HHCP metabolites were found in similar abundance as the monohydroxy metabolites. All of the bishydroxylated metabolites besides a minor metabolite had a hydroxyl group on the side chain and another hydroxyl group on the alicyclic part of the molecule. In addition, the corresponding glucuronides were identified by LC-HR-MS/MS. The exact positions and stereochemistry of the hydroxylation sites could not be determined. Due to the extensive metabolism of HHCP and the lacking cross-reactivity of urine samples after consumption in Δ-THC specific immunoassays, it is recommended to include HHCP metabolites in routine screening methods. Monohydroxylated and bishydroxylated metabolites of HHCP and their respective glucuronides are suggested as forensic targets.
六氢大麻酚（HHCP）是一种新兴的半合成大麻素，自1942年对四氢大麻酚（THC）类似物和同系物的研究中就已为人所知。在许多欧洲国家禁止六氢大麻酚（HHC）后，HHCP作为其他类似化合物的替代品出现。一些国家已将HHCP纳入其麻醉药品法。本研究的目的是确定口服HHCP后尿液中的人体I期和II期代谢产物。一名已戒除Δ-THC的志愿者单次口服4毫克HHCP后，对尿液样本进行的酶免疫分析检测结果显示大麻素呈阴性。自我实验中使用的HHCP样本购自一家网店，并预先使用气相色谱-质谱联用仪（GC-MS）进行了分析。液相色谱-高分辨质谱联用仪（LC-HR-MS/MS）和衍生化后的GC-MS用于代谢产物的鉴定。发现了羟基化代谢产物，其羟基化发生在分子的侧链或脂环部分。发现双羟基化的HHCP代谢产物的丰度与单羟基代谢产物相似。除一种次要代谢产物外，所有双羟基化代谢产物在分子的侧链上有一个羟基，在脂环部分有另一个羟基。此外，通过LC-HR-MS/MS鉴定出了相应的葡糖醛酸苷。羟基化位点的确切位置和立体化学无法确定。由于HHCP的广泛代谢以及在特定的Δ-THC免疫分析中食用后尿液样本缺乏交叉反应性，建议在常规筛查方法中纳入HHCP代谢产物。HHCP的单羟基化和双羟基化代谢产物及其各自的葡糖醛酸苷被建议作为法医鉴定的目标。
