Abstract
Recently, there has been a rise in abuse of synthetic cannabinoids (SCBs). The consumption of SCBs results in various effects and can induce toxic reactions, including paranoia, seizures, tachycardia and even death. 1-Naphthyl 1-(4-fluorobenzyl)-1H-indole-3-carboxylate (FDU-PB-22) is a third generation SCB whose metabolic pathway has not been fully characterized.
In this study, we conducted in vitro pharmacokinetic analysis of FDU-PB-22 metabolism.
Metabolic reactions containing FDU-PB-22 and human liver microsomes (HLMs) were independent of NADPH but not UDP-glucuronic acid (UDPGA), suggesting that UDP-glucuronosyltransferases (UGTs) are the primary enzymes involved in this metabolism. It was further determined that the metabolite extensively formed after incubating FDU-PB-22 with UDPGA in HLMs was the glucuronide of FDU-PB-22 3-carboxyindole (FBI-COOH). Various hepatic UGTs showed enzymatic activity for FBI-COOH. A series of UGT inhibitors showed moderate to strong inhibition of FBI-COOH-glucuronidation in HLMs, suggesting that multiple UGT isoforms are involved in FBI-COOH-glucuronidation in the liver. Interestingly, an extra-hepatic isoform, UGT1A10, exhibited the highest activity with a Km value of 38 µM and a Vmax value of 5.90 nmol/min/mg.
Collectively, these results suggest that both genetic mutations of and the co-administration of inhibitors for FDU-PB-22-metabolizing UGTs will likely increase the risk of FDU-PB-22-induced toxicity.
Acknowledgments
We thank Dr. Susan A. Kadlubar (Division of Medical Genetics) and Dr. L. Joseph Su (College of Public Health) at University of Arkansas for Medical Sciences (UAMS) for their support and valuable discussion and Dr. Moshe Finel (University of Helsinki, Finland) for providing us the recombinant UGTs. Sabrina Jones was a student in the Summer Research Internship Program (SRIP) through the UAMS Center for Diversity Affairs in 2018.
Disclosure statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.