Inhibition of cytochrome P450 and uridine 50-diphosphoglucuronosyltransferases by MAM-2201 in human liver microsomes

다국어 초록 (Multilingual Abstract)

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.

참고문헌 (Reference)

1 Auwarter V, "‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs?" 44 : 832-837, 2009

2 Uchiyama N, "URB-754: a new class of designer drug and 12 synthetic cannabinoids detected in illegal products" 227 : 21-32, 2013

3 Kronstrand R, "Toxicological findings of synthetic cannabinoids in recreational users" 37 : 534-541, 2013

4 Alonen A, "The human UDPglucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan" 76 : 763-772, 2008

5 Chung H, "Synthetic cannabinoids abused in South Korea: drug identifications by the National Forensic Service from 2009 to June 2013" 32 : 82-88, 2014

6 Andreeva-Gateva PA, "Synthetic cannabimimetics in Bulgaria 2010-2013" 157 : 200-204, 2015

7 Derungs A, "Symptoms, toxicities, and analytical results for a patient after smoking herbs containing the novel synthetic cannabinoid MAM-2201" 31 : 164-171, 2013

8 Zhou SF, "Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development" 16 : 3480-3675, 2009

9 Seely KA, "Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids" 39 : 234-243, 2012

10 Erichsen TJ, "Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids" 52 : 570-578, 2010

11 공태연, "Rapid analysis of drugs of abuse and their metabolites in human urine using dilute and shoot liquid chromatography–tandem mass spectrometry" 대한약학회 40 (40): 180-196, 2017

12 Cerny MA, "Prevalence of non–cytochrome P450–mediated metabolism in Food and Drug Administration–approved oral and intravenous drugs: 2006–2015" 44 : 1246-1252, 2016

13 Yamaori S, "Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety" 88 : 730-736, 2011

14 Zaitsu K, "Metabolome disruption of the rat cerebrum induced by the acute toxic effects of the synthetic cannabinoid MAM-2201" 137 : 49-55, 2015

15 Su MK, "Metabolism of classical cannabinoids and the synthetic cannabinoid JWH-018" 97 : 562-564, 2015

16 Kong TY, "Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes" 409 : 1667-1680, 2017

17 Polasek TM, "Mechanismbased inactivation of human cytochrome P4502C8 by drugs in vitro" 311 : 996-1007, 2004

18 Lonati D, "MAM-2201 (analytically confirmed) intoxication after ‘‘Synthacaine’’consumption" 64 : 629-632, 2014

19 Al Saabi A, "Involvement of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 in ethanol glucuronidation, and interactions with common drugs of abuse" 41 : 568-574, 2013

20 Kwon SS, "Inhibitory effects of aschantin on cytochrome P450 and uridine 50-diphospho-glucuronosyltransferase enzyme activities in human liver microsomes" 21 : E554-, 2016

21 Roth MD, "Induction and regulation of the carcinogenmetabolizing enzyme CYP1A1 by marijuana smoke and delta (9)-tetrahydrocannabinol" 24 : 339-344, 2001

22 Kim JH, "In vitro metabolism of a novel synthetic cannabinoid, EAM-2201, in human liver microsomes and human recombinant cytochrome P450s" 119 : 50-58, 2016

23 Uchiyama N, "Identification of a novel cannabimimetic phenylacetylindole, cannabipiperidiethanone, as a designer drug in a herbal product and its affinity for cannabinoid CB1 and CB2 receptors" 59 : 1203-1205, 2011

24 Uchiyama N, "Identification of a cannabinoid analog as a new type of designer drug in a herbal product" 57 : 439-441, 2009

25 Nakajima JI, "Identification and quantitation of a benzoylindole (2-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone and a naphthoylindole 1-(5-fluoropentyl-1H-indol-3-yl)-(naphthalene-1-yl)methanone (AM-2201) found in illegal products obtained via the Internet and their cannabimimetic effects evaluated by in vitro [35S]GTPcS binding assays" 29 : 132-141, 2011

26 Langer N, "Identification and quantification of synthetic cannabinoids in ‘spice-like’ herbal mixtures: a snapshot of the German situation in the autumn of 2012" 6 : 59-71, 2014

27 Lai XS, "Human CYP2C8: structure, substrate specificity, inhibitor selectivity, inducers and polymorphisms" 10 : 1009-1047, 2009

28 Zaitsu K, "High-resolution mass spectrometric determination of the synthetic cannabinoids MAM-2201, AM-2201, AM-2232, and their metabolites in postmortem plasma and urine by LC/Q-TOFMS" 129 : 1233-1245, 2015

29 Jeong ES, "Glucuronidation of fimasartan, a new angiotensin receptor antagonist, is mainly mediated by UGT1A3" 45 : 10-18, 2015

30 Stout SM, "Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review" 46 : 86-95, 2014

31 Zhou SF, "Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4" 9 : 310-322, 2008

32 Musshoff F, "Driving under the influence of synthetic cannabinoids (‘‘Spice’’): a case series" 128 : 59-64, 2014

33 Yamaori S, "Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids" 29 : 117-124, 2011

34 Helander A, "Detection of new psychoactive substance use among emergency room patients: results from the Swedish STRIDA project" 243 : 23-29, 2014

35 Tomiyama KI, "Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death" 274 : 17-23, 2014

36 Chimalakonda KC, "Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands" 40 : 2174-2184, 2012

37 Zanger UM, "Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation" 138 : 103-141, 2013

38 Foti RS, "Cytochrome P450 and non–cytochrome P450 oxidative metabolism: contributions to the pharmacokinetics, safety, and efficacy of xenobiotics" 44 : 1229-1245, 2016

39 Yamaori S, "Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity" 27 : 294-300, 2012

40 Yamaori S, "Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes" 79 : 1691-1698, 2010

41 Zendulka O, "Cannabinoids and cytochrome P450 interactions" 17 : 206-226, 2016

42 Yamaori S, "Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6" 39 : 2049-2056, 2011

43 Fattore L, "Beyond THC: the new generation of cannabinoid designer drugs" 5 : 60-, 2011

44 Tournebize J, "Acute effects of synthetic cannabinoids: update 2015" 11 : 1-23, 2016

45 Kim JH, "AM-2201 inhibits multiple cytochrome P450 and uridine 50-diphospho-glucuronosyltransferase enzyme activities in human liver microsomes" 22 : E443-, 2017

46 Saito T, "A fatal case of MAM-2201 poisoning" 31 : 333-337, 2013