Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Drug Metab Dispos. 2011 Oct;39(10):1967-76. doi: 10.1124/dmd.111.040709. Epub 2011 Jul 11.
K2, a synthetic cannabinoid (SC), is an emerging drug of abuse touted as "legal marijuana" and marketed to young teens and first-time drug users. Symptoms associated with K2 use include extreme agitation, syncope, tachycardia, and visual and auditory hallucinations. One major challenge to clinicians is the lack of clinical, pharmacological, and metabolic information for the detection and characterization of K2 and its metabolites in human samples. Information on the metabolic pathway of SCs is very limited. However, previous reports have shown the metabolites of these compounds are excreted primarily as glucuronic acid conjugates. Based on this information, this study evaluates nine human recombinant uridine diphosphate-glucuronosyltransferase (UGT) isoforms and human liver and intestinal microsomes for their ability to glucuronidate hydroxylated metabolites of 1-naphthalenyl-1(1-pentyl-1H-indol-3-yl)-methanone (JWH-018) and (1-butyl-1H-indol-3-yl)-1-naphthalenyl-methanone (JWH-073), the two most common SCs found in K2 products. Conjugates were identified and characterized using liquid chromatography/tandem mass spectrometry, whereas kinetic parameters were quantified using high-performance liquid chromatography-UV-visible methods. UGT1A1, UGT1A3, UGT1A9, UGT1A10, and UGT2B7 were shown to be the major enzymes involved, showing relatively high affinity with K(m) ranging from 12 to 18 μM for some hydroxylated K2s. These UGTs also exhibited a high metabolic capacity for these compounds, which indicates that K2 metabolites may be rapidly glucuronidated and eliminated from the body. Studies of K2 metabolites will help future development and validation of a specific assay for K2 and its metabolites and will allow researchers to fully explore their pharmacological actions.
K2 是一种合成大麻素（SC），作为“合法大麻”被吹捧为新兴的滥用药物，面向青少年和初次吸毒者销售。使用 K2 会引起的症状包括极度激动、晕厥、心动过速以及视觉和听觉幻觉。临床医生面临的一个主要挑战是缺乏关于 K2 及其代谢物在人体样本中的检测和特征描述的临床、药理学和代谢信息。关于 SC 代谢途径的信息非常有限。然而，以前的报告表明，这些化合物的代谢物主要作为葡萄糖醛酸缀合物排泄。基于此信息，本研究评估了九个人类重组尿苷二磷酸-葡萄糖醛酸基转移酶（UGT）同工型以及人肝和肠微粒体，以评估它们对 1-萘基-1（1-戊基-1H-吲哚-3-基）-甲酮（JWH-018）和（1-丁基-1H-吲哚-3-基）-1-萘基-甲酮（JWH-073）羟基化代谢物进行葡萄糖醛酸化的能力，这两种是 K2 产品中最常见的 SC。使用液相色谱/串联质谱法鉴定和表征缀合物，而使用高效液相色谱-紫外可见法定量测定动力学参数。结果表明，UGT1A1、UGT1A3、UGT1A9、UGT1A10 和 UGT2B7 是主要涉及的酶，对某些羟基化 K2 的亲和力相对较高，K(m) 值范围为 12 至 18 μM。这些 UGT 对这些化合物也表现出较高的代谢能力，这表明 K2 代谢物可能会迅速葡萄糖醛酸化并从体内消除。对 K2 代谢物的研究将有助于未来开发和验证针对 K2 及其代谢物的特定检测方法，并使研究人员能够充分探索它们的药理学作用。
