AKB48 and its fluorinated derivative 5F-AKB48 are synthetic cannabinoids (SCs) which have caused hospitalizations and deaths in human users. Abuse of SCs is dangerous because users may mistake them for natural cannabis, which is generally considered to be unlikely to elicit adverse effects. The present studies were designed to investigate the in vitro oxidative metabolism of 5F-AKB48 by human microsomal fractions from different organs and sexes as well as recombinant human cytochrome P450s (P450s). Mass spectrometry data tentatively provides evidence for the existence of mono-, di-, and trihydroxylated metabolites in a successive metabolism. Experiments utilizing P450s revealed that the most active enzymes (CYP2D6, CYP2J2, CYP3A4, and CYP3A5) effectively produced mono- and dihydroxylated metabolites, while CYP3A4/5 also produced significant amounts of the trihydroxylated metabolite. Moreover, although the affinity and potency of Phase I metabolite 4OH-5F-AKB48 is reduced when compared to that of the parent drug, this metabolite nevertheless retains similar high affinity for CB1 receptors, and greater efficacy for G protein activation, when compared to THC. Finally, 5F-AKB48 produced time- and dose-dependent cannabimimetic effects in mice which were more potent, but shorter acting, than those of Δ⁹-THC, and were attenuated by prior treatment with the CB1 antagonist rimonabant. Based on our data, we hypothesize that while many cases of toxicity result from genetic mutations, which can lead to a decrease or even absence of activity for Phase I drug-metabolizing enzymes, other P450s could potentially increase their role in the metabolism of these SCs. Because many metabolites of SCs remain biologically active, they could contribute to the deleterious effects of these substances.

AKB48 及其氟化衍生物 5F-AKB48 是合成大麻素 (SC)，已导致人类使用者住院和死亡。滥用 SCs 是危险的，因为使用者可能会将它们误认为天然大麻，这通常被认为不太可能引起不利影响。本研究旨在研究来自不同器官和性别的人微粒体部分以及重组人细胞色素 P450s (P450s) 对 5F-AKB48 的体外氧化代谢。质谱数据暂时为连续代谢中存在单羟基、二羟基和三羟基代谢物提供了证据。利用 P450 的实验表明，最活跃的酶（CYP2D6、CYP2J2、CYP3A4 和 CYP3A5）有效地产生单羟基和二羟基代谢物，而 CYP3A4/5 也产生了大量的三羟基化代谢物。此外，虽然与母体药物相比，I 期代谢物 4OH-5F-AKB48 的亲和力和效力有所降低，但与 THC 相比，该代谢物仍保留了与 CB1 受体相似的高亲和力，以及对 G 蛋白激活的更高功效. 最后，5F-AKB48 在小鼠中产生了时间和剂量依赖性的大麻模拟作用，与 Δ 相比，这种作用更有效，但作用更短。^9- THC，并通过先前用 CB1 拮抗剂利莫那班治疗减弱。根据我们的数据，我们假设，虽然许多毒性病例是由基因突变引起的，这可能导致 I 期药物代谢酶的活性降低甚至消失，但其他 P450 可能会增加它们在这些 SCs 代谢中的作用. 因为 SCs 的许多代谢物仍然具有生物活性，它们可能会导致这些物质的有害影响。