Cannabinoid Metabolites as Inhibitors of Major Hepatic CYP450 Enzymes, with Implications for Cannabis-Drug Interactions.
Cannabinoid Metabolites as Inhibitors of Major Hepatic CYP450 Enzymes, with Implications for Cannabis-Drug Interactions.
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DOI：
10.1124/dmd.121.000442
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发表时间：
2021-12-01
期刊：
影响因子：
--
通讯作者：
Lazarus, Philip
中科院分区：
文献类型：
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作者：
Nasrin, Shamema;Watson, Christy J W;Lazarus, Philip
大麻在美国许多地区和其他国家合法化，导致需要更全面地了解大麻成分及其药物相互作用的可能性。虽然（-）-反式-Δ 9-四氢大麻酚（THC）、大麻二酚（CBD）和大麻酚（CBN）是大麻中存在的最丰富的大麻素，但在血浆中发现的THC代谢物浓度更高，持续时间比母体大麻素更长。为了了解药物相互作用的可能性，检查了主要大麻素及其代谢产物对主要肝细胞色素P450（P450）酶的抑制潜力。用P450过表达细胞微粒体进行的体外试验表明，主要THC代谢物11-羟基-Δ 9-四氢大麻酚和11-去甲-9-羧基-Δ 9-THC-葡糖苷酸竞争性抑制几种主要的P450酶，包括CYP 2B 6、CYP 2C 9和CYP 2D 6（表观Ki，u值分别为0.086 ± 0.066 M和0.90 ± 0.54 M，0.057 ± 0.044 M和2.1 ± 0.81 M，0.15 ± 0.067 M和2.3 ± 0.54 M）。11-Nor-9-carboxy-Delta 9- tetrahydrocannabinol对任何受试CYP 450均未显示抑制活性。THC竞争性抑制CYP 1A 2、CYP 2B 6、CYP 2C 9和CYP 2D 6; CBD竞争性抑制CYP 3A 4、CYP 2B 6、CYP 2C 9、CYP 2D 6和CYP 2 E1; CBN竞争性抑制CYP 2B 6、CYP 2C 9和CYP 2 E1。THC和CBD分别对CYP 2C 19和CYP 1A 2具有混合型抑制作用。这些数据表明，大麻素和主要的THC代谢物能够抑制多种P450酶的活性，这些数据的基本静态建模表明，这些大麻素和被CYP 2B 6、CYP 2C 9和CYP 2D 6广泛代谢的外源性物质之间可能存在药代动力学相互作用。重要性声明：大麻使用者血浆中发现的主要大麻素及其代谢物抑制几种P450酶，包括CYP 2B 6，CYP 2C 9和CYP 2D 6。这项研究首次显示了最丰富的血浆大麻素代谢物THC-COO-Gluc的抑制潜力，并表明大麻素的循环代谢物在CYP 450酶抑制以及药物相互作用中发挥重要作用。
The legalization of cannabis in many parts of the United States and other countries has led to a need for a more comprehensive understanding of cannabis constituents and their potential for drug-drug interactions. Although (-)-trans-Delta9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are the most abundant cannabinoids present in cannabis, THC metabolites are found in plasma at higher concentrations and for a longer duration than that of the parent cannabinoids. To understand the potential for drug-drug interactions, the inhibition potential of major cannabinoids and their metabolites on major hepatic cytochrome P450 (P450) enzymes was examined. In vitro assays with P450-overexpressing cell microsomes demonstrated that the major THC metabolites 11-hydroxy-Delta9-tetra-hydrocannabinol and 11-nor-9-carboxy-Delta9-THC-glucuronide competitively inhibited several major P450 enzymes, including CYP2B6, CYP2C9, and CYP2D6 (apparent Ki,u values = 0.086 ± 0.066 M and 0.90 ± 0.54 M, 0.057 ± 0.044 M and 2.1 ± 0.81 M, 0.15 ± 0.067 M and 2.3 ± 0.54 M, respectively). 11-Nor-9-carboxy-Delta9- tetrahydrocannabinol exhibited no inhibitory activity against any CYP450 tested. THC competitively inhibited CYP1A2, CYP2B6, CYP2C9, and CYP2D6; CBD competitively inhibited CYP3A4, CYP2B6, CYP2C9, CYP2D6, and CYP2E1; and CBN competitively inhibited CYP2B6, CYP2C9, and CYP2E1. THC and CBD showed mixed-type inhibition for CYP2C19 and CYP1A2, respectively. These data suggest that cannabinoids and major THC metabolites are able to inhibit the activities of multiple P450 enzymes, and basic static modeling of these data suggest the possibility of pharmacokinetic interactions between these cannabinoids and xenobiotics extensively metabolized by CYP2B6, CYP2C9, and CYP2D6. SIGNIFICANCE STATEMENT: Major cannabinoids and their metabolites found in the plasma of cannabis users inhibit several P450 enzymes, including CYP2B6, CYP2C9, and CYP2D6. This study is the first to show the inhibition potential of the most abundant plasma cannabinoid metabolite, THC-COO-Gluc, and suggests that circulating metabolites of cannabinoids play an essential role in CYP450 enzyme inhibition as well as drug-drug interactions.