Synthetic cannabinoids are substrates and inhibitors of multiple drug-metabolizing enzymes
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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.
KeywordsCannabinoids Metabolism Cytochrome P450 UDP-glucuronosyltransferases Drug interaction
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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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