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

作者：Kim Ju Hyun; Kwon Soon Sang; Kong Tae Yeon; Cheong Jae Chul; Kim Hee Seung; In Moon Kyo; Lee Hye Suk^*

来源：Molecules, 2017, 22(3): 443.

DOI：10.3390/molecules22030443

• AM-2201
• cytochrome P450 inhibition
• UDP-glucuronosyltransferase inhibition
• human liver microsomes
• drug-drug interaction

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 mu M, respectively, and showed mechanism-based inhibition of CYP2C8-catalyzed amodiaquine N-deethylation with a K-i value of 2.1 mu M. It negligibly inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, and UGT1A9 activities at 50 M 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.

• 出版日期2017-3