CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48

Abstract

Abstract. Synthetic cannabinoid designer drugs have emerged as drugs of abuse during the last decade, and acute intoxication cases are documented in the scientific literature. Synthetic cannabinoids are extensively metabolized, but our knowledge of the involved enzymes is limited. Here, we investigated the metabolism of N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48), a compound identified in herbal blends from 2012 and onwards. We screened for metabolite formation using a panel of nine recombinant cytochrome P450 (CYP) enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4) and compared the formed metabolites to human liver microsomal (HLM) incubations with specific inhibitors against CYP2D6, 2C19, and 3A4, respectively. The data reported here demonstrate CYP3A4 to be the major CYP enzyme responsible for the oxidative metabolism of AKB-48, preferentially performing the oxidation on the adamantyl moiety. Genetic polymorphisms are likely not important with regard to toxicity given the major involvement of CYP3A4. Adverse drug-drug interactions (DDIs) could potentially occur in cases with co-intake of strong CYP3A4 inhibitors, e.g., HIV antivirals and azole antifungal agents.

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“…Without this information, understanding of adverse drug reactions potentially related to polymorphisms of drug metabolizing enzymes and drug-drug interactions cannot be achieved. For example, CYP1A2 and CYP2C9 are the major cytochrome P450 enzymes responsible for metabolism of the SCB JWH-018 [158], while CYP3A4 is most important for oxidation of AKB-48 [162]. SCBs of the napthoylindole class inhibit [163], while cigarette smoking induce [164], CYP1A activity.…”

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“…[14] After 10 min of pre-incubation of the compound with pHLM, the reactions were then started by addition of the NADPH regenerating system consisting of Glucuronidation in pHLM was investigated by following a previously published procedure. [15] Here, the enzymatic reactions were commenced by the addition of UDPGA and alamethicin at the final concentrations of 2 mM and 25 µg/mL, respectively, with and without presence of NADPH.…”

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“…Major metabolites of 5F-AB-PINACA were AB-PINACA pentanoic acid, 5'-hydroxypentyl-AB-PINACA, and 5F-AB-PINACA carboxylic acid (Wohlfarth et al, 2015). AKB-48 is predominantly metabolized by human hepatocytes by mono-, di-, and trihydroxylation on the adamantyl ring followed by glucuronidation (Ghandi et al, 2013;Holm et al, 2015).…”