Advertisement

Archives of Pharmacal Research

, Volume 41, Issue 7, pp 691–710 | Cite as

Synthetic cannabinoids are substrates and inhibitors of multiple drug-metabolizing enzymes

  • Tae Yeon Kong
  • Ju-Hyun Kim
  • Dong Kyun Kim
  • Hye Suk LeeEmail author
Review
  • 497 Downloads

Abstract

Synthetic cannabinoids, a new class of psychoactive substances, are potent agonists of cannabinoid receptors, which mimic the psychoactive effects of the principal psychoactive component of cannabis, ∆9-tetrahydrocannabinol. Despite governmental scheduling as illicit drugs, new synthetic cannabinoids are being produced. The abuse of synthetic cannabinoids with several drugs containing different chemical groups has resulted in large numbers of poisonings. This has increased the urgency for forensic and public health laboratories to identify the metabolites of synthetic cannabinoids and apply this knowledge to the development of analytical methods and for toxicity prediction. It is necessary to determine whether synthetic cannabinoids are involved in drug-metabolizing enzyme-mediated drug–drug interactions. This review describes the metabolic pathways of 13 prevalent synthetic cannabinoids and various drug-metabolizing enzymes responsible for their metabolism, including cytochrome P450 (CYP), UDP-glucuronosyltransferases (UGTs), and carboxylesterases. The inhibitory effects of synthetic cannabinoids on CYP and UGT activities are also reviewed to predict the potential of synthetic cannabinoids for drug–drug interactions. The drug-metabolizing enzymes responsible for metabolism of synthetic cannabinoids should be characterized and the effects of synthetic cannabinoids on CYP and UGT activities should be determined to predict the pharmacokinetics of synthetic cannabinoids and synthetic cannabinoid-induced drug–drug interactions in the clinic.

Keywords

Cannabinoids Metabolism Cytochrome P450 UDP-glucuronosyltransferases Drug interaction 

Notes

Acknowledgements

This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (NRF-2015M3A9E1028325).

Compliance with ethical standards

Conflicts of interest

The authors declare no conflict of interest.

References

  1. Adamowicz P, Gieron J (2016) Acute intoxication of four individuals following use of the synthetic cannabinoid MAB-CHMINACA. Clin Toxicol (Phila) 54:650–654CrossRefGoogle Scholar
  2. Adamowicz P, Zuba D, Sekula K (2013) Analysis of UR-144 and its pyrolysis product in blood and their metabolites in urine. Forensic Sci Int 233:320–327PubMedCrossRefGoogle Scholar
  3. Al Saabi A, Allorge D, Sauvage FL, Tournel G, Gaulier JM, Marquet P, Picard N (2013) Involvement of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 in ethanol glucuronidation, and interactions with common drugs of abuse. Drug Metab Dispos 41:568–574PubMedCrossRefGoogle Scholar
  4. Alexander SP (2016) Therapeutic potential of cannabis-related drugs. Prog Neuropsychopharmacol Biol Psychiatry 64:157–166PubMedCrossRefGoogle Scholar
  5. Andreeva-Gateva PA, Nankova VH, Angelova VT, Gatev TN (2015) Synthetic cannabimimetics in Bulgaria 2010-2013. Drug Alcohol Depend 157:200–204PubMedCrossRefGoogle Scholar
  6. Arellano AL, Papaseit E, Romaguera A, Torrens M, Farre M (2017) Neuropsychiatric and general interactions of natural and synthetic cannabinoids with drugs of abuse and medicines. CNS Neurol Disord 16:554–566CrossRefGoogle Scholar
  7. Ashino T, Hakukawa K, Itoh Y, Numazawa S (2014) Inhibitory effect of synthetic cannabinoids on CYP1A activity in mouse liver microsomes. J Toxicol Sci 39:815–820PubMedCrossRefGoogle Scholar
  8. Badowski ME (2017) A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and pharmacodynamics. Cancer Chemother Pharmacol 80:441–449PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bilici R (2014) Synthetic cannabinoids. North Clin Istanb 1:121–126PubMedPubMedCentralCrossRefGoogle Scholar
  10. Borgelt LM, Franson KL, Nussbaum AM, Wang GS (2013) The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 33:195–209PubMedCrossRefGoogle Scholar
  11. Cannaert A, Storme J, Franz F, Auwarter V, Stove CP (2016) Detection and activity profiling of synthetic cannabinoids and their metabolites with a newly developed bioassay. Anal Chem 88:11476–11485PubMedCrossRefGoogle Scholar
  12. Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S, Huestis MA (2014) Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications. Drug Alcohol Depend 144:12–41PubMedCrossRefGoogle Scholar
  13. Castaneto MS, Wohlfarth A, Desrosiers NA, Hartman RL, Gorelick DA, Huestis MA (2015a) Synthetic cannabinoids pharmacokinetics and detection methods in biological matrices. Drug Metab Rev 47:124–174PubMedCrossRefGoogle Scholar
  14. Castaneto MS, Wohlfarth A, Pang S, Zhu M, Scheidweiler KB, Kronstrand R, Huestis MA (2015b) Identification of AB-FUBINACA metabolites in human hepatocytes and urine using high-resolution mass spectrometry. Forensic Toxicol 33:295–310CrossRefGoogle Scholar
  15. Cerny MA (2016) Prevalence of non-cytochrome P450-mediated metabolism in food and drug administration-approved oral and intravenous drugs: 2006–2015. Drug Metab Dispos 44(8):1246–1252.  https://doi.org/10.1124/dmd.116.070763 PubMedCrossRefGoogle Scholar
  16. Chimalakonda KC, Bratton SM, Le VH, Yiew KH, Dineva A, Moran CL, James LP, Moran JH, Radominska-Pandya A (2011) Conjugation of synthetic cannabinoids JWH-018 and JWH-073, metabolites by human UDP-glucuronosyltransferases. Drug Metab Dispos 39:1967–1976PubMedPubMedCentralCrossRefGoogle Scholar
  17. Chimalakonda KC, Seely KA, Bratton SM, Brents LK, Moran CL, Endres GW, James P, Hollenberg PF, Prather PL, Radominska-Pandya A, Moran JH (2012) Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos 40:2174–2784PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chimalakonda KC, James LP, Radominska-Pandya A, Moran JH (2013) Sulfaphenazole and alpha-naphthoflavone attenuate the metabolism of the synthetic cannabinoids JWH-018 and AM2201 found in K2/spice. Drug Metab Lett 7:34–38PubMedPubMedCentralCrossRefGoogle Scholar
  19. Cooper ZD, Poklis JL, Liu F (2017) Methodology for controlled administration of smoked synthetic cannabinoids JWH-018 and JWH-073. Neuropharmacology.  https://doi.org/10.1016/j.neuropharm.2017.11.020 PubMedCrossRefGoogle Scholar
  20. Derungs A, Schwaninger AE, Mansella G, Bingisser R, Kraemer T, Liechti ME (2013) Symptoms, toxicities, and analytical results for a patient after smoking herbs containing the novel synthetic cannabinoid MAM-2201. Forensic Toxicol 31:164–171CrossRefGoogle Scholar
  21. Diao X, Huestis MA (2017) Approaches, challenges, and advances in metabolism of new synthetic cannabinoids and identification of optimal urinary marker metabolites. Clin Pharmacol Ther 101:239–253PubMedCrossRefGoogle Scholar
  22. Diao X, Scheidweiler KB, Wohlfarth A, Pang S, Kronstrand R, Huestis MA (2016) In vitro and in vivo human metabolism of synthetic cannabinoids FDU-PB-22 and FUB-PB-22. AAPS J 18:455–464PubMedPubMedCentralCrossRefGoogle Scholar
  23. ElSohly MA, Gul W, Elsohly KM, Murphy TP, Madgula VL, Khan SI (2011) Liquid chromatography-tandem mass spectrometry analysis of urine specimens for K2 (JWH-018) metabolites. J Anal Toxicol 35(7):487–495PubMedCrossRefGoogle Scholar
  24. Elsohly MA, Gul W, Wanas AS, Radwan MM (2014) Synthetic cannabinoids: analysis and metabolites. Life Sci 97:78–90PubMedCrossRefGoogle Scholar
  25. Erratico C, Negreira N, Norouzizadeh H, Covaci A, Neels H, Maudens K, van Nuijs AL (2015) In vitro and in vivo human metabolism of the synthetic cannabinoid AB-CHMINACA. Drug Test Anal 7(10):866–876PubMedCrossRefGoogle Scholar
  26. Fattore L, Fratta W (2011) Beyond THC: the new generation of cannabinoid designer drugs. Front Behav Neurosci 5:60PubMedPubMedCentralCrossRefGoogle Scholar
  27. Fisar Z (2009) Phytocannabinoids and endocannabinoids. Curr Drug Abuse Rev 2:51–75PubMedCrossRefGoogle Scholar
  28. Foti RS, Dalvie DK (2016) Cytochrome P450 and non-cytochrome P450 oxidative metabolism: contributions to the pharmacokinetics, safety, and efficacy of xenobiotics. Drug Metab Dispos 44:1229–1245PubMedCrossRefGoogle Scholar
  29. Fraguas-Sanchez AI, Fernandez-Carballido A, Torres-Suarez AI (2016) Phyto-, endo- and synthetic cannabinoids: promising chemotherapeutic agents in the treatment of breast and prostate carcinomas. Expert Opin Investig Drugs 25:1311–1323PubMedCrossRefGoogle Scholar
  30. Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD (2010) Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity. J Med Chem 53:295–315PubMedCrossRefGoogle Scholar
  31. Gambaro V, Arnoldi S, Bellucci S, Casagni E, Dell’Acqua L, Fumagalli L, Pallavicini M, Roda G, Rusconi C, Valoti E (2014) Characterization of in vitro metabolites of JWH-018, JWH-073 and their 4-methyl derivatives, markers of the abuse of these synthetic cannabinoids. J Chromatogr B 957:68–76CrossRefGoogle Scholar
  32. Gandhi AS, Zhu M, Pang S, Wohlfarth A, Scheidweiler KB, Liu HF, Huestis MA (2013) First characterization of AKB-48 metabolism, a novel synthetic cannabinoid, using human hepatocytes and high-resolution mass spectrometry. AAPS J 15:1091–1098PubMedPubMedCentralCrossRefGoogle Scholar
  33. Giuffrida A, McMahon LR (2010) In vivo pharmacology of endocannabinoids and their metabolic inhibitors: therapeutic implications in Parkinson’s disease and abuse liability. Prostaglandins Other Lipid Mediat 91:90–103PubMedCrossRefGoogle Scholar
  34. Grigoryev A, Kavanagh P, Melnik A, Savchuk S, Simonov A (2013) Gas and liquid chromatography-mass spectrometry detection of the urinary metabolites of UR-144 and its major pyrolysis product. J Anal Toxicol 37:265–276PubMedGoogle Scholar
  35. Harris CR, Brown A (2013) Synthetic cannabinoid intoxication: a case series and review. The J Emerg Med 44:360–366PubMedCrossRefGoogle Scholar
  36. Helander A, Backberg M, Hulten P, Al-Saffar Y, Beck O (2014) Detection of new psychoactive substance use among emergency room patients: results from the Swedish STRIDA project. Forensic Sci Int 243:23–29PubMedCrossRefGoogle Scholar
  37. Hermanns-Clausen M, Kneisel S, Szabo B, Auwärter V (2013) Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings. Addiction 108:534–544PubMedCrossRefGoogle Scholar
  38. Hess C, Stockhausen S, Kernbach-Wighton G, Madea B (2015) Death due to diabetic ketoacidosis: induction by the consumption of synthetic cannabinoids? Forensic Sci Int 257:e6–e11PubMedCrossRefGoogle Scholar
  39. Hess C, Murach J, Krueger L, Scharrenbroch L, Unger M, Madea B, Sydow K (2017) Simultaneous detection of 93 synthetic cannabinoids by liquid chromatography-tandem mass spectrometry and retrospective application to real forensic samples. Drug Test Anal 9:721–733PubMedCrossRefGoogle Scholar
  40. Holm NB, Nielsen LM, Linnet K (2015) CYP3A4 mediates oxidative metabolism of the synthetic cannabinoid AKB-48. AAPS J 17:1237–1245PubMedPubMedCentralCrossRefGoogle Scholar
  41. Holm NB, Noble C, Linnet K (2016) JWH-018 omega-OH, a shared hydroxy metabolite of the two synthetic cannabinoids JWH-018 and AM-2201, undergoes oxidation by alcohol dehydrogenase and aldehyde dehydrogenase enzymes in vitro forming the carboxylic acid metabolite. Toxicol Lett 259:35–43PubMedCrossRefGoogle Scholar
  42. Jang M, Yang W, Choi H, Chang H, Lee S, Kim E, Chung H (2013) Monitoring of urinary metabolites of JWH-018 and JWH-073 in legal cases. Forensic Sci Int 231:13–19PubMedCrossRefGoogle Scholar
  43. Jang M, Yang W, Shin I, Choi H, Chang H, Kim E (2014a) Determination of AM-2201 metabolites in urine and comparison with JWH-018 abuse. Int J Legal Med 128:285–294PubMedCrossRefGoogle Scholar
  44. Jang M, Shin I, Yang W, Chang H, Yoo HH, Lee J, Kim E (2014b) Determination of major metabolites of MAM-2201 and JWH-122 in in vitro and in vivo studies to distinguish their intake. Forensic Sci Int 244:85–91PubMedCrossRefGoogle Scholar
  45. Jang M, Shin I, Kim J, Yang W (2015) Simultaneous quantification of 37 synthetic cannabinoid metabolites in human urine by liquid chromatography-tandem mass spectrometry. Forensic Toxicol 33:221–234CrossRefGoogle Scholar
  46. Jang M, Kim IS, Park YN, Kim J, Han I, Baeck S, Yang W, Yoo HH (2016) Determination of urinary metabolites of XLR-11 by liquid chromatography-quadrupole time-of-flight mass spectrometry. Anal Bioanal Chem 408:503–516PubMedCrossRefGoogle Scholar
  47. Ji Nakajima, Takahashi M, Nonaka R, Seto T, Suzuki J, Yoshida M, Kanai C, Hamano T (2011) 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]GTPγS binding assays. Forensic Toxicol 29:132–141CrossRefGoogle Scholar
  48. Jiang R, Yamaori S, Okamoto Y, Yamamoto I, Watanabe K (2013) Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet 28:332–338PubMedCrossRefGoogle Scholar
  49. Kanamori T, Kanda K, Yamamuro T, Kuwayama K, Tsujikawa K, Iwata YT, Inoue H (2015) Detection of main metabolites of XLR-11 and its thermal degradation product in human hepatoma HepaRG cells and human urine. Drug Test Anal 7:341–345PubMedCrossRefGoogle Scholar
  50. Karila L, Benyamina A, Blecha L, Cottencin O, Billieux J (2016) The synthetic cannabinoids phenomenon. Curr Pharm Des 22:6420–6425PubMedCrossRefGoogle Scholar
  51. Kavanagh P, Grigoryev A, Savchuk S, Mikhura I, Formanovsky A (2013) UR-144 in products sold via the Internet: identification of related compounds and characterization of pyrolysis products. Drug Test Anal 5:683–692PubMedCrossRefGoogle Scholar
  52. Kim J, Park Y, Park M, Kim E, Yang W, Baeck S, Lee S, Han S (2015) Simultaneous determination of five naphthoylindole-based synthetic cannabinoids and metabolites and their deposition in human and rat hair. J Pharm Biomed Anal 102:162–175PubMedCrossRefGoogle Scholar
  53. Kim JH, Kim HS, Kong TY, Lee JY, Kim JY, In MK, Lee HS (2016) In vitro metabolism of a novel synthetic cannabinoid, EAM-2201, in human liver microsomes and human recombinant cytochrome P450s. J Pharm Biomed Anal 119:50–58PubMedCrossRefGoogle Scholar
  54. Kim JH, Kwon SS, Jeong HU, Lee HS (2017a) Inhibitory effects of dimethyllirioresinol, epimagnolin a, eudesmin, fargesin, and magnolin on cytochrome P450 enzyme activities in human liver microsomes. Int J Mol Sci 18:E952PubMedCrossRefGoogle Scholar
  55. Kim JH, Kwon SS, Kong TY, Cheong JC, Kim HS, In MK, Lee HS (2017b) AM-2201 inhibits multiple cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferase enzyme activities in human liver microsomes. Molecules 22:E443PubMedCrossRefGoogle Scholar
  56. Kim JH, Kong TY, Moon JY, Choi KH, Cho YY, Kang HC, Lee JY, Lee HS (2018) Targeted and non-targeted metabolite identification of MAM-2201 in human, mouse, and rat hepatocytes. Drug Test Anal.  https://doi.org/10.1002/dta.2389 CrossRefPubMedGoogle Scholar
  57. Kong TY, Kim J-H, Choi WG, Lee JY, Kim HS, Kim JY, In MK, Lee HS (2017a) 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. Anal Bioanal Chem 409:1667–1680PubMedCrossRefGoogle Scholar
  58. Kong TY, Kim JH, Kim JY, In MK, Choi KH, Kim HS, Lee HS (2017b) Rapid analysis of drugs of abuse and their metabolites in human urine using dilute and shoot liquid chromatography-tandem mass spectrometry. Arch Pharm Res 40:180–196PubMedCrossRefGoogle Scholar
  59. Kong TY, Kim JH, Kwon SS, Cheong JC, Kim HS, In MK, Lee HS (2017c) Inhibition of cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferases by MAM-2201 in human liver microsomes. Arch Pharm Res 40:727–735PubMedCrossRefGoogle Scholar
  60. Kong TY, Kwon SS, Cheong JC, Kim HS, Kim JY, Lee HS (2018) In vitro inhibitory effects of synthetic cannabinoid EAM-2201 on cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in human liver microsomes. Molecules 23:E920PubMedCrossRefGoogle Scholar
  61. Kronstrand R, Roman M, Andersson M, Eklund A (2013) Toxicological findings of synthetic cannabinoids in recreational users. J Anal Toxicol 37:534–541PubMedCrossRefGoogle Scholar
  62. Lonati D, Buscaglia E, Papa P, Valli A, Coccini T, Giampreti A, Petrolini VM, Vecchio S, Serpelloni G, Locatelli CA (2014) MAM-2201 (analytically confirmed) intoxication after “Synthacaine” consumption. Ann Emerg Med 64:629–632PubMedCrossRefGoogle Scholar
  63. Marusich JA, Wiley JL, Lefever TW, Patel PR, Thomas BF (2017) Finding order in chemical chaos—continuing characterization of synthetic cannabinoid receptor agonists. Neuropharmacology.  https://doi.org/10.1016/j.neuropharm.2017.10.041 PubMedCrossRefGoogle Scholar
  64. McQuade D, Hudson S, Dargan PI, Wood DM (2013) First European case of convulsions related to analytically confirmed use of the synthetic cannabinoid receptor agonist AM-2201. Eur J Clin Pharmacol 69:373–376PubMedCrossRefGoogle Scholar
  65. Mills B, Yepes A, Nugent K (2015) Synthetic cannabinoids. Am J Med Sci 350:59–62PubMedCrossRefGoogle Scholar
  66. Musshoff F, Madea B, Kernbach-Wighton G, Bicker W, Kneisel S, Hutter M, Auwarter V (2014) Driving under the influence of synthetic cannabinoids (“Spice”): a case series. Int J Legal Med 128:59–64PubMedCrossRefGoogle Scholar
  67. Na DH, Ji HY, Park EJ, Kim MS, Liu KH, Lee HS (2011) Evaluation of metabolism-mediated herb-drug interactions. Arch Pharm Res 34:1829–1842PubMedCrossRefGoogle Scholar
  68. Nielsen LM, Holm NB, Olsen L, Linnet K (2016) Cytochrome P450-mediated metabolism of the synthetic cannabinoids UR-144 and XLR-11. Drug Test Anal 8:792–800PubMedCrossRefGoogle Scholar
  69. Ozturk S, Ozturk YE, Yeter O, Alpertunga B (2015) Application of a validated LC-MS/MS method for JWH-073 and its metabolites in blood and urine in real forensic cases. Forensic Sci Int 257:165–171PubMedCrossRefGoogle Scholar
  70. Park M, Yeon S, Lee J, In S (2015) Determination of XLR-11 and its metabolites in hair by liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal 114:184–189PubMedCrossRefGoogle Scholar
  71. Patton AL, Chimalakonda KC, Moran CL, McCain KR, Radominska‐Pandya A, James LP, Kokes C, Moran JH (2013) K2 toxicity: fatal case of psychiatric complications following AM2201 exposure. J Forensic Sci 58:1676–1680PubMedPubMedCentralCrossRefGoogle Scholar
  72. Peterson BL, Couper FJ (2015) Concentrations of AB-CHMINACA and AB-PINACA and driving behavior in suspected impaired driving cases. J Anal Toxicol 39:642–647PubMedCrossRefGoogle Scholar
  73. Poklis JL, Amira D, Wise LE, Wiebelhaus JM, Haggerty BJ, Poklis A (2012a) Detection and disposition of JWH-018 and JWH-073 in mice after exposure to “Magic Gold” smoke. Forensic Sci Int 220:91–96PubMedPubMedCentralCrossRefGoogle Scholar
  74. Poklis JL, Amira D, Wise LE, Wiebelhaus JM, Haggerty BJ, Lichtman AH, Poklis A (2012b) Determination of naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) in mouse blood and tissue after inhalation exposure to ‘buzz’ smoke by HPLC/MS/MS. Biomed Chromatogr 26:1393–1398PubMedPubMedCentralCrossRefGoogle Scholar
  75. Presley BC, Gurney SM, Scott KS, Kacinko SL, Logan BK (2016) Metabolism and toxicological analysis of synthetic cannabinoids in biological fluids and tissues. Forensic Sci Rev 28:103–169PubMedGoogle Scholar
  76. Richter LHJ, Maurer HH, Meyer MR (2017) New psychoactive substances: studies on the metabolism of XLR-11, AB-PINACA, FUB-PB-22, 4-methoxy-alpha-PVP, 25-I-NBOMe, and meclonazepam using human liver preparations in comparison to primary human hepatocytes, and human urine. Toxicol Lett 280:142–150PubMedCrossRefGoogle Scholar
  77. Roth MD, Marques-Magallanes JA, Yuan M, Sun W, Tashkin DP, Hankinson O (2001) Induction and regulation of the carcinogen-metabolizing enzyme CYP1A1 by marijuana smoke and delta (9)-tetrahydrocannabinol. Am J Respir Cell Mol Biol 24:339–344PubMedCrossRefGoogle Scholar
  78. Saito T, Namera A, Miura N, Ohta S, Miyazaki S, Osawa M, Inokuchi S (2013) A fatal case of MAM-2201 poisoning. Forensic Toxicol 31:333–337CrossRefGoogle Scholar
  79. Satoh T, Taylor P, Bosron WF, Sanghani SP, Hosokawa M, La Du BN (2002) Current progress on esterases: from molecular structure to function. Drug Metab Dispos 30:488–493PubMedCrossRefGoogle Scholar
  80. Schneir AB, Baumbacher T (2012) Convulsions associated with the use of a synthetic cannabinoid product. J Med Toxicol 8:62–64PubMedCrossRefGoogle Scholar
  81. Seely KA, Lapoint J, Moran JH, Fattore L (2012) Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 39:234–243PubMedPubMedCentralCrossRefGoogle Scholar
  82. Sim J, Cho HS, Lee J, In S, Kim E (2017) Determination of AB-CHMINACA and its metabolites in human hair and their deposition in hair of abusers. J Pharm Biomed Anal 140:162–168PubMedCrossRefGoogle Scholar
  83. Sobolevsky T, Prasolov I, Rodchenkov G (2012) Detection of urinary metabolites of AM-2201 and UR-144, two novel synthetic cannabinoids. Drug Test Anal 4:745–753PubMedCrossRefGoogle Scholar
  84. Sobolevsky T, Prasolov I, Rodchenkov G (2015) Study on the phase I metabolism of novel synthetic cannabinoids, APICA and its fluorinated analogue. Drug Test Anal 7:131–142PubMedCrossRefGoogle Scholar
  85. Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev 46:86–95PubMedCrossRefGoogle Scholar
  86. Su MK, Seely KA, Moran JH, Hoffman RS (2015) Metabolism of classical cannabinoids and the synthetic cannabinoid JWH-018. Clin Pharmacol Ther 97:562–564PubMedCrossRefGoogle Scholar
  87. Tai S, Fantegrossi WE (2017) Pharmacological and toxicological effects of synthetic cannabinoids and their metabolites. Curr Top Behav Neurosci 32:249–262PubMedPubMedCentralCrossRefGoogle Scholar
  88. Takayama T, Suzuki M, Todoroki K, Inoue K, Min JZ, Kikura-Hanajiri R, Goda Y, Toyo’oka T (2014) UPLC/ESI-MS/MS-based determination of metabolism of several new illicit drugs, ADB-FUBINACA, AB-FUBINACA, AB-PINACA, QUPIC, 5F-QUPIC and alpha-PVT, by human liver microsome. Biomed Chromatogr 28:831–838PubMedCrossRefGoogle Scholar
  89. Thomsen R, Nielsen LM, Holm NB, Rasmussen HB, Linnet K (2015) Synthetic cannabimimetic agents metabolized by carboxylesterases. Drug Test Anal 7:565–576PubMedCrossRefGoogle Scholar
  90. Toennes SW, Geraths A, Pogoda W, Paulke A, Wunder C, Theunissen EL, Ramaekers JG (2017) Pharmacokinetic properties of the synthetic cannabinoid JWH-018 and of its metabolites in serum after inhalation. J Pharm Biomed Anal 140:215–222PubMedCrossRefGoogle Scholar
  91. Toennes SW, Geraths A, Pogoda W, Paulke A, Wunder C, Theunissen EL, Ramaekers JG (2018a) Pharmacokinetic properties of the synthetic cannabinoid JWH-018 in oral fluid after inhalation. Drug Test Anal 10:644–650PubMedCrossRefGoogle Scholar
  92. Toennes SW, Geraths A, Pogoda W, Paulke A, Wunder C, Theunissen EL, Ramaekers JG (2018b) Excretion of metabolites of the synthetic cannabinoid JWH-018 in urine after controlled inhalation. J Pharm Biomed Anal 150:162–168PubMedCrossRefGoogle Scholar
  93. Tomiyama K, Funada M (2014) Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death. Toxicol Appl Pharmacol 274:17–23PubMedCrossRefGoogle Scholar
  94. Tournebize J, Gibaja V, Kahn JP (2017) Acute effects of synthetic cannabinoids: update 2015. Subst Abuse 38:344–366CrossRefGoogle Scholar
  95. Vallersnes OM, Persett PS, Oiestad EL, Karinen R, Heyerdahl F, Hovda KE (2017) Underestimated impact of novel psychoactive substances: laboratory confirmation of recreational drug toxicity in Oslo, Norway. Clin Toxicol (Phila) 55:636–644CrossRefGoogle Scholar
  96. Vikingsson S, Josefsson M, Green H (2015) Identification of AKB-48 and 5F-AKB-48 metabolites in authentic human urine samples using human liver microsomes and time of flight mass spectrometry. J Anal Toxicol 39:426–435PubMedCrossRefGoogle Scholar
  97. Vikingsson S, Green H, Brinkhagen L, Mukhtar S, Josefsson M (2016) Identification of AB-FUBINACA metabolites in authentic urine samples suitable as urinary markers of drug intake using liquid chromatography quadrupole tandem time of flight mass spectrometry. Drug Test Anal 8:950–956PubMedCrossRefGoogle Scholar
  98. Wintermeyer A, Moller I, Thevis M, Jübner M, Beike J, Rothschild MA, Bender K (2010) In vitro phase I metabolism of the synthetic cannabimimetic JWH-018. Anal Bioanal Chem 398:2141–2153PubMedCrossRefGoogle Scholar
  99. Wohlfarth A, Pang S, Zhu M, Gandhi AS, Scheidweiler KB, Liu HF, Huestis MA (2013) First metabolic profile of XLR-11, a novel synthetic cannabinoid, obtained by using human hepatocytes and high-resolution mass spectrometry. Clin Chem 59:1638–1648PubMedPubMedCentralCrossRefGoogle Scholar
  100. Wohlfarth A, Gandhi AS, Pang S, Zhu M, Scheidweiler KB, Huestis MA (2014) Metabolism of synthetic cannabinoids PB-22 and its 5-fluoro analog, 5F-PB-22, by human hepatocyte incubation and high-resolution mass spectrometry. Anal Bioanal Chem 406:1763–1780PubMedCrossRefGoogle Scholar
  101. Wohlfarth A, Castaneto MS, Zhu M, Pang S, Scheidweiler KB, Kronstrand R, Huestis MA (2015) Pentylindole/pentylindazole synthetic cannabinoids and their 5-fluoro analogs produce different primary metabolites: metabolite profiling for AB-PINACA and 5F-AB-PINACA. AAPS J 17:660–677PubMedPubMedCentralCrossRefGoogle Scholar
  102. Wurita A, Hasegawa K, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Suzuki O, Watanabe K (2016) Identification and quantification of metabolites of AB-CHMINACA in a urine specimen of an abuser. Leg Med (Tokyo) 19:113–118CrossRefGoogle Scholar
  103. Yamaori S, Kushihara M, Yamamoto I, Watanabe K (2010) Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes. Biochem Pharmacol 79:1691–1698PubMedCrossRefGoogle Scholar
  104. Yamaori S, Maeda C, Yamamoto I, Watanabe K (2011a) Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids. Forensic Toxicol 29(2):117–124CrossRefGoogle Scholar
  105. Yamaori S, Okamoto Y, Yamamoto I, Watanabe K (2011b) Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos 39:2049–2056PubMedCrossRefGoogle Scholar
  106. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K (2011c) Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci 88:730–736PubMedCrossRefGoogle Scholar
  107. Yamaori S, Koeda K, Kushihara M, Hada Y, Yamamoto I, Watanabe K (2012) Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet 27:294–300PubMedCrossRefGoogle Scholar
  108. Zaitsu K, Nakayama H, Yamanaka M, Hisatsune K, Taki K, Asano T, Kamata T, Katagai M, Hayashi Y, Kusano M, Tsuchihashi H, Ishii A (2015) 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. Int J Legal Med 129:1233–1245PubMedCrossRefGoogle Scholar
  109. Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138:103–141PubMedCrossRefGoogle Scholar
  110. Zendulka O, Dovrtelova G, Noskova K, Turjap M, Sulcova A, Hanus L, Jurica J (2016) Cannabinoids and cytochrome P450 interactions. Curr Drug Metab 17:206–226PubMedCrossRefGoogle Scholar
  111. Znaleziona J, Ginterova P, Petr J, Ondra P, Valka I, Sevcik J, Chrastina J, Maier V (2015) Determination and identification of synthetic cannabinoids and their metabolites in different matrices by modern analytical techniques—a review. Anal Chim Acta 874:11–25PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2018

Authors and Affiliations

  • Tae Yeon Kong
    • 1
  • Ju-Hyun Kim
    • 2
  • Dong Kyun Kim
    • 1
  • Hye Suk Lee
    • 1
    Email author
  1. 1.BK21 PLUS Team for Creative Leader Program for Pharmacomics-Based Future Pharmacy and Drug Metabolism and Bioanalysis Laboratory, College of PharmacyThe Catholic University of KoreaBucheonRepublic of Korea
  2. 2.Department of Pharmacology, College of MedicineDongguk UniversityGyeongjuRepublic of Korea

Personalised recommendations