부산대학교 도서관

MAM-2201, a synthetic cannabinoid, is a potentagonist of the cannabinoid receptors and is increasinglyused as an illicit recreational drug. The inhibitory effects ofMAM-2201 on major drug-metabolizing enzymes such ascytochrome P450s (CYPs) and uridine 50-diphospho-glucuronosyltransferases(UGTs) have not yet been investigatedalthough it is widely abused, sometimes incombination with other drugs. We evaluated the inhibitoryeffects of MAM-2201 on eight major human CYPs (CYPs1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and sixUGTs (UGTs 1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) ofpooled human liver microsomes; we thus explored potentialMAM-2201-induced drug interactions. MAM-2201potently inhibited CYP2C9-catalyzed diclofenac 40-hydroxylation,CYP3A4-catalyzed midazolam 10-hydroxylation,and UGT1A3-catalyzed chenodeoxycholic acid24-acyl-glucuronidation, with Ki values of 5.6, 5.4 and5.0 lM, respectively. MAM-2201 exhibited mechanismbasedinhibition of CYP2C8-catalyzed amodiaquine N-deethylationwith Ki and kinact values of 1.0 lM and0.0738 min-1, respectively. In human liver microsomes,MAM-2201 (50 lM) negligibly inhibited CYP1A2,CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1,UGT1A4, UGT1A6, UGT1A9, and UGT2B7. Based onthese in vitro results, we conclude that MAM-2201 has thepotential to trigger in vivo pharmacokinetic drug interactionswhen co-administered with substrates of CYP2C8,CYP2C9, CYP3A4, and UGT1A3.