title: Conjugation of synthetic cannabinoids JWH-018 and JWH-073, metabolites by human UDP-glucuronosyltransferases.
abstract: 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.
authors: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors: Krishna C
authors: KC
authors: Chimalakonda
authors: Stacie M
authors: SM
authors: Bratton
authors: Vi-Huyen
authors: VH
authors: Le
authors: Kan Hui
authors: KH
authors: Yiew
authors: Anna
authors: A
authors: Dineva
authors: Cindy L
authors: CL
authors: Moran
authors: Laura P
authors: LP
authors: James
authors: Jeffery H
authors: JH
authors: Moran
authors: Anna
authors: A
authors: Radominska-Pandya
mesh_terms: D002186:Cannabinoids / Q000378:metabolism*; D002853:Chromatography, Liquid / Q000379:methods; D020723:Glucuronic Acid / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007211:Indoles / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000201:enzymology; D007700:Kinetics; D013058:Mass Spectrometry / Q000379:methods; D050217:Metabolic Detoxication, Phase II; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism*; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D002186:Cannabinoids; D007211:Indoles; D009281:Naphthalenes; D020033:Protein Isoforms; D011994:Recombinant Proteins; D020723:Glucuronic Acid; C568258:JWH-073; D014453:Glucuronosyltransferase; C552597:1-pentyl-3-(1-naphthoyl)indole