Kong Tae Yeon, Kwon Soon-Sang, Cheong Jae Chul, Kim Hee Seung, Kim Jin Young, Lee Hye Suk
BK21 PLUS Team for Creative Leader Program for Pharmacomics-Based Future Pharmacy, Drug Metabolism & Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 14462, Korea.
Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul 06590, Korea.
Molecules. 2018 Apr 16;23(4):920. doi: 10.3390/molecules23040920.
EAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors that is widely abused as an illicit recreational drug in combination with other drugs. To evaluate the potential of EAM-2201 as a perpetrator of drug−drug interactions, the inhibitory effects of EAM-2201 on major drug-metabolizing enzymes, cytochrome P450s (CYPs) and uridine 5′-diphospho-glucuronosyltransferases (UGTs) were evaluated in pooled human liver microsomes using liquid chromatography−tandem mass spectrometry (LC-MS/MS). EAM-2201 at doses up to 50 µM negligibly inhibited the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and five UGTs (1A1, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes. EAM-2201 exhibited time-dependent inhibition of CYP2C8-catalyzed amodiaquine -deethylation, CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP2C19-catalyzed []-mephenytoin 4′-hydroxylation and CYP3A4-catalyzed midazolam 1′-hydroxylation with values of 0.54 µM (: 0.0633 min), 3.0 µM (: 0.0462 min), 3.8 µM (: 0.0264 min) and 4.1 µM (: 0.0250 min), respectively and competitively inhibited UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, with a value of 2.4 µM. Based on these in vitro results, we conclude that EAM-2201 has the potential to trigger in vivo pharmacokinetic drug interactions when co-administered with substrates of CYP2C8, CYP2C9, CYP2C19, CYP3A4 and UGT1A3.
EAM - 2201是一种合成大麻素，是大麻素受体的强效激动剂，常与其他药物混合作为非法娱乐性药物被广泛滥用。为了评估EAM - 2201引发药物相互作用的可能性，采用液相色谱 - 串联质谱法（LC - MS/MS）在人肝微粒体混合液中评估了EAM - 2201对主要药物代谢酶细胞色素P450（CYP）和尿苷5'-二磷酸葡萄糖醛酸转移酶（UGT）的抑制作用。在人肝微粒体中，剂量高达50 µM的EAM - 2201对8种主要人CYP（1A2、2A6、2B6、2C8、2C9、2C19、2D6和3A4）和5种UGT（1A1、1A4、1A6、1A9和2B7）的活性抑制作用可忽略不计。EAM - 2201对CYP2C8催化的阿莫地喹去乙基化、CYP2C9催化的双氯芬酸4'-羟基化、CYP2C19催化的[]-美芬妥英4'-羟基化以及CYP3A4催化的咪达唑仑1'-羟基化表现出时间依赖性抑制作用，其抑制常数分别为0.54 µM（: 0.0633分钟）、3.0 µM（: 0.0462分钟）、3.8 µM（: 0.0264分钟）和4.1 µM（: 0.0250分钟），并且对UGT1A3催化的鹅去氧胆酸24 - 酰基葡萄糖醛酸化具有竞争性抑制作用，抑制常数为2.4 µM。基于这些体外实验结果，我们得出结论，当EAM - 2201与CYP2C8、CYP2C9、CYP2C19、CYP3A4和UGT1A3的底物共同给药时，有引发体内药代动力学药物相互作用的可能性。
