AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5'-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes.

Ju-Hyun Kim,Moon In,Tae Kong,Jae Cheong,Hye Lee,Soon-Sang Kwon,Hee Kim

doi:10.3390/molecules22030443

Abstract

AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) enzymes in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry to investigate drug interaction potentials of AM-2201. AM-2201 potently inhibited CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP3A4-catalyzed midazolam 1′-hydroxylation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, and UGT2B7-catalyzed naloxone 3-glucuronidation with IC50 values of 3.9, 4.0, 4.3, and 10.0 µM, respectively, and showed mechanism-based inhibition of CYP2C8-catalyzed amodiaquine N-deethylation with a Ki value of 2.1 µM. It negligibly inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, and UGT1A9 activities at 50 μM in human liver microsomes. These in vitro results indicate that AM-2201 needs to be examined for potential pharmacokinetic drug interactions in vivo due to its potent inhibition of CYP2C8, CYP2C9, CYP3A4, UGT1A3, and UGT2B7 enzyme activities.

Highlights

Synthetic cannabinoids are a group of substances with functionally similar effects to∆9-tetrahydrocannabinol (THC), which is responsible for the major psychoactive effects of cannabis, and generally bind to cannabinoid receptor type 1 (CB1 ) or 2 (CB2 ) [1]
JWH-018 was first detected in herbal smoking mixtures, called Spice, in 2008; 160 synthetic cannabinoids are monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) through the EU Early Warning System [2]
As AM-2201 is extensively metabolized [19], its metabolites may inhibit cytochrome P450 (CYP) and uridine -diphospho-glucuronosyltransferase (UGT) activities. These in vitro results suggest that AM-2201 should be examined in terms of potential in vivo pharmacokinetic drug interactions caused by inhibition of CYP2C8, CYP2C9, CYP3A4, UGT1A3, and UGT2B7 activities

Summary

Introduction

Synthetic cannabinoids are a group of substances with functionally similar effects to. ∆9-tetrahydrocannabinol (THC), which is responsible for the major psychoactive effects of cannabis, and generally bind to cannabinoid receptor type 1 (CB1 ) or 2 (CB2 ) [1]. JWH-018 was first detected in herbal smoking mixtures, called Spice, in 2008; 160 synthetic cannabinoids are monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) through the EU Early Warning System [2]. AM-2201 (Figure 1) is a third-generation synthetic cannabinoid, modified by introduction of a fluorine atom to JWH compounds, and exerts potent pharmacological actions on brain function, causing psychoactive and intoxicating effects [10]. Molecules 2017, 22, 443; doi:10.3390/molecules22030443 www.mdpi.com/journal/molecules compounds, and exerts potent pharmacological actions on brain function, causing psychoactive and intoxicating effects [10].

Methods

Results

Conclusion