title: AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5'-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes.
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.
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, Korea. jhyunkim@catholic.ac.kr.
authors.forename: Ju-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, Korea. zuzutnseo@naver.com.
authors.forename: Soon-Sang
authors.initials: SS
authors.lastname: Kwon
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, Korea. kongtaeyun@naver.com.
authors.forename: Tae Yeon
authors.initials: TY
authors.lastname: Kong
authors.affiliation: Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul 06590, Korea. Saturn-jjc@spo.go.kr.
authors.forename: Jae Chul
authors.initials: JC
authors.lastname: Cheong
authors.affiliation: Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul 06590, Korea. hskjay@spo.go.kr.
authors.forename: Hee Seung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Forensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor's Office, 157 Banpo-daero, Seocho-gu, Seoul 06590, Korea. inmk@spo.go.kr.
authors.forename: Moon Kyo
authors.initials: MK
authors.lastname: In
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, Korea. sianalee@catholic.ac.kr.
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007527:Isoenzymes; D008862:Microsomes, Liver / Q000201:enzymology*; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: C582337:1-(5-fluoropentyl)-3-(1-naphthoyl)indole; D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D009281:Naphthalenes; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase
keywords: AM-2201; UDP-glucuronosyltransferase inhibition; cytochrome P450 inhibition; drug-drug interaction; human liver microsomes