title: Sulfaphenazole and α-naphthoflavone attenuate the metabolism of the synthetic cannabinoids JWH-018 and AM2201 found in K2/spice.
abstract: "K2" or "Spice" is an emerging drug of abuse that is laced with psychoactive synthetic cannabinoids JWH-018 and AM2201. Previous studies have identified hydroxylated (OH) and carboxylated (COOH) species as primary human metabolites, and kinetic studies have implicated CYP2C9 and -1A2 as major hepatic P450s involved in JWH-018 and AM2201 oxidation. The present study extends these findings by testing the hypothesis that CYP2C9- and 1A2-selective chemical inhibitors, sulfaphenazole (SFZ) and α-naphthoflavone (ANF), block oxidation of JWH-018 and AM2201 in human liver microsomes (HLM). A concentration-dependent inhibition of JWH-018 and AM2201 oxidation was observed in the presence of increasing concentration of SFZ (0.5 - 50 μM) and ANF (0.1 - 5.0 μM). No metabolic inhibition was observed with omeprazole, quinidine, and ketoconazole. The results presented herein further demonstrate the importance of CYP2C9- and 1A2-mediated oxidation of JWH-018 and AM2201 and the likelihood of adverse toxicity in populations with polymorphic alleles of these enzymes.
authors: Krishna C
authors: KC
authors: Chimalakonda
authors: Laura P
authors: LP
authors: James
authors: Anna
authors: A
authors: Radominska-Pandya
authors: Arkansas Department of Health, Public Health Laboratory, 201 S. Monroe Street, Little Rock, AR, 72205, USA. jeffery.moran@arkansas.gov.
authors: Jeffery H
authors: JH
authors: Moran
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001571:Benzoflavones / Q000494:pharmacology*; D002186:Cannabinoids / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D013287:Illicit Drugs; D007211:Indoles / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D013426:Sulfaphenazole / Q000494:pharmacology*
chemical_list: C582337:1-(5-fluoropentyl)-3-(1-naphthoyl)indole; D000890:Anti-Infective Agents; D001571:Benzoflavones; D002186:Cannabinoids; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D013287:Illicit Drugs; D007211:Indoles; D009281:Naphthalenes; D013426:Sulfaphenazole; C011512:alpha-naphthoflavone; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2; C552597:1-pentyl-3-(1-naphthoyl)indole