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Conjugation of synthetic cannabinoids JWH-018 and JWH-073, metabolites by human UDP-glucuronosyltransferases.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2011 Oct; Vol. 39 (10), pp. 1967-76. Date of Electronic Publication: 2011 Jul 11. - Publication Year :
- 2011
-
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.
- Subjects :
- Chromatography, Liquid methods
Glucuronic Acid metabolism
Humans
Hydroxylation
Intestinal Mucosa metabolism
Intestines enzymology
Kinetics
Mass Spectrometry methods
Metabolic Detoxication, Phase II
Microsomes enzymology
Microsomes metabolism
Microsomes, Liver enzymology
Microsomes, Liver metabolism
Protein Isoforms
Recombinant Proteins metabolism
Cannabinoids metabolism
Glucuronosyltransferase metabolism
Indoles metabolism
Naphthalenes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-009X
- Volume :
- 39
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 21746969
- Full Text :
- https://doi.org/10.1124/dmd.111.040709