Kong Tae Yeon, Kim Ju-Hyun, Kwon Soon-Sang, Cheong Jae Chul, Kim Hee Seung, In Moon Kyo, Lee Hye Suk
Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, Gyeonggi-do, 14662, Republic of Korea.
Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul, 06590, Republic of Korea.
Arch Pharm Res. 2017 Jun;40(6):727-735. doi: 10.1007/s12272-017-0917-y. Epub 2017 May 8.
MAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors and is increasingly used as an illicit recreational drug. The inhibitory effects of MAM-2201 on major drug-metabolizing enzymes such as cytochrome P450s (CYPs) and uridine 5'-diphospho-glucuronosyltransferases (UGTs) have not yet been investigated although it is widely abused, sometimes in combination with other drugs. We evaluated the inhibitory effects of MAM-2201 on eight major human CYPs (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six UGTs (UGTs 1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) of pooled human liver microsomes; we thus explored potential MAM-2201-induced drug interactions. MAM-2201 potently inhibited CYP2C9-catalyzed diclofenac 4'-hydroxylation, CYP3A4-catalyzed midazolam 1'-hydroxylation, and UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, with K values of 5.6, 5.4 and 5.0 µM, respectively. MAM-2201 exhibited mechanism-based inhibition of CYP2C8-catalyzed amodiaquine N-de-ethylation with K and k values of 1.0 µM and 0.0738 min, respectively. In human liver microsomes, MAM-2201 (50 µM) negligibly inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7. Based on these in vitro results, we conclude that MAM-2201 has the potential to trigger in vivo pharmacokinetic drug interactions when co-administered with substrates of CYP2C8, CYP2C9, CYP3A4, and UGT1A3.
MAM - 2201是一种合成大麻素，是大麻素受体的强效激动剂，越来越多地被用作非法娱乐性药物。尽管MAM - 2201被广泛滥用，有时还与其他药物联合使用，但其对主要药物代谢酶如细胞色素P450（CYP）和尿苷5'-二磷酸葡萄糖醛酸转移酶（UGT）的抑制作用尚未得到研究。我们评估了MAM - 2201对人肝微粒体中8种主要人类CYP（CYP 1A2、2A6、2B6、2C8、2C9、2C19、2D6和3A4）和6种UGT（UGT 1A1、1A3、1A4、1A6、1A9和2B7）的抑制作用；因此，我们探究了MAM - 2201诱导药物相互作用的可能性。MAM - 2201强烈抑制CYP2C9催化的双氯芬酸4'-羟基化、CYP3A4催化的咪达唑仑1'-羟基化以及UGT1A3催化的鹅去氧胆酸24 - 酰基葡萄糖醛酸化，其K值分别为5.6、5.4和5.0 μM。MAM - 2201对CYP2C8催化的阿莫地喹N - 去乙基化表现出基于机制的抑制作用，其K和k值分别为1.0 μM和0.0738 min⁻¹。在人肝微粒体中，MAM - 2201（50 μM）对CYP1A2、CYP2A6、CYP2B6、CYP2C19、CYP2D6、UGT1A1、UGT1A4、UGT1A6、UGT1A9和UGT2B7的抑制作用可忽略不计。基于这些体外实验结果，我们得出结论，当MAM - 2201与CYP2C8、CYP2C9、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。
