TY - JOUR T1 - Conjugation of Synthetic Cannabinoids, JWH-018 [Naphthalen-1-yl-(1-pentylindol-3-yl)methanone] and JWH-073 [naphthalen-1-yl-(1-butylindol-3-yl)methanone], Metabolites by Human UDP-glucuronosyltransferases JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.040709 SP - dmd.111.040709 AU - Krishna C. Chimalakonda AU - Stacie M. Bratton AU - Vi-Huyen Le AU - Kan Hui Nicole Yiew AU - Anna Dineva AU - Cindy L. Moran AU - Laura P. James AU - Jeffery H. Moran AU - Anna Radominska-Pandya Y1 - 2011/07/11 UR - http://dmd.aspetjournals.org/content/early/2011/07/11/dmd.111.040709.abstract N2 - 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, 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 9 human recombinant uridine diphosphate-glucuronosyltransferase (UGT) isoforms, and human liver and intestinal microsomes for their ability to glucuronidate hydroxylated metabolites of JWH-018 and JWH-073, the two most common SCs found in K2 products. Conjugates were identified and characterized, using LC-MS/MS, while kinetic parameters were quantified using HPLC-UV/Vis methods. UGT1A1, 1A3, 1A9, 1A10 and 2B7 were shown to be major enzymes involved, showing relatively high affinity with Kms ranging from 12-18 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. ER -