Conjugation of synthetic cannabinoids in K2/Spice by human UDP‐glucuronosyltransferase (UGTs)

K2, a synthetic cannabinoid, is an emerging drug of abuse touted as “legal marijuana” and marketed to young teens and first time drug users who have been shown to experience extreme agitation, syncope, tachycardia, visual and auditory hallucinations. One major challenge to physicians is the lack of a clinical assay for detection of K2 and its metabolites in human samples. This study evaluates 9 human recombinant UGT isoforms, and human liver and intestinal microsomes for their ability to glucuronidate hydroxylated metabolites of the two most commonly observed K2 compounds, JWH‐018 [naphthalen‐1‐yl‐(1‐pentylindol‐3‐yl)methanone] and JWH‐073 [naphthalen‐1‐yl‐(1‐butylindol‐3‐yl)methanone]. Conjugates were identified, characterized, and quantified using HPLC and LC‐MS/MS. UGT1A1 and 1A9 (liver), and UGT1A10 (intestine) were shown to be the major enzymes involved. Activity was also detected with isoforms found in brain and lung. Kinetic constants show relatively high affinity (some K m s in the range of 12–18 μM) and capacity of UGTs for oxidized K2s indicating that these compounds may be rapidly glucuronidated and eliminated from the body. Studies of K2 metabolites will help in the development and validation of a specific assay for K2 and its metabolites and will allow researchers to fully explore their pharmacological actions. (NIH‐GM075893 to AR‐P; APHL Innovation Award to JM)