三种市售大麻素产品对 ATP 结合盒式转运蛋白和溶质载体转运蛋白功能的筛查。
Screening of Three Commercial Cannabis-Based Products on ATP-Binding Cassette and Solute-Carrier Transporter Function.
机构信息
Brain and Mind Centre, The University of Sydney, Sydney, Australia.
Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, Australia.
出版信息
Cannabis Cannabinoid Res. 2022 Jun;7(3):304-317. doi: 10.1089/can.2020.0053. Epub 2020 Sep 22.
Legalization of medicinal cannabis around the world has led to an increase in the use of commercial cannabis-based products in the community. These cannabis-based products are being used in combination with conventional drugs to treat a variety of health conditions. Moreover, recreational cannabis-based products may be used in combination with other drugs. In this setting, there is increased potential for drug-drug interactions (DDIs) involving commercial cannabis-based products. Since DDIs can lead to serious adverse events, drug regulatory bodies require that every investigational drug be evaluated for DDI potential at metabolic enzymes and transporters. However, this seldom occurs for cannabis-based products due to legislation in many jurisdictions allowing a direct pathway to market. This study aimed to examine the inhibitory potential of three commercially available cannabis-based products at human ATP-binding cassette (ABC) and solute-carrier (SLC) transporters. Three commercial cannabis-based products (Spectrum Yellow™, Tweed Argyle, and Spectrum Red™) that contain differing concentrations of cannabidiol (CBD) and Δ-tetrahydrocannabinol (Δ-THC) were evaluated for DDI potential at 12 drug transporters. HEK293 cells or vesicles expressing human ABC transporters (ABCB1, ABCC2, ABCG2, or ABCB11) and SLC transporters (SLC22A1, SLC22A2, SLC22A6, SLC22A8, SLCO1B1, SLCO1B3, SLC47A1, and SLC47A2) were used to measure transporter function. Spectrum Yellow and Tweed Argyle inhibited ABCG2 transporter function. The IC value of Spectrum Yellow based on CBD and Δ-THC content was 4.5 μM for CBD and 0.20 μM for Δ-THC, and the IC value of Tweed Argyle was 9.3 μM for CBD and 6.0 μM for Δ-THC. Tweed Argyle also inhibited ABCB11 transporter function with an IC value of 11.9 μM for CBD and 7.7 μM for Δ-THC. SLC22A6, SLC22A1, SLC22A2, SLCO1B1, and SLCO1B3 transporter functions were modestly inhibited by high concentrations of the cannabis-based products. The three cannabis-based products did not inhibit ABCB1, ABCC2, SLC47A1, SLC47A2, or SLC22A8 transporters. Novel findings were that the cannabis-based products inhibited ABCB11, SLC22A6, SLC22A1, SLC22A2, SLCO1B1, and SLCO1B3 (although modestly in most instances). Spectrum Yellow and Tweed Argyle potently inhibited ABCG2, and future DDI studies could be conducted to assess whether cannabis products affect the pharmacokinetics of medications that are ABCG2 substrates.
世界各地医用大麻的合法化导致社区中商业大麻类产品的使用增加。这些大麻类产品正与传统药物联合用于治疗各种健康状况。此外，娱乐用大麻类产品可能与其他药物联合使用。在这种情况下，涉及商业大麻类产品的药物-药物相互作用（DDI）的可能性增加。由于 DDI 可能导致严重的不良事件，药物监管机构要求对每一种研究药物的代谢酶和转运体的 DDI 潜力进行评估。然而，由于许多司法管辖区的立法允许直接进入市场，因此这种情况很少发生在大麻类产品上。本研究旨在研究三种市售大麻类产品对人三磷酸腺苷结合盒（ABC）和溶质载体（SLC）转运体的抑制潜力。 评估了三种市售大麻类产品（Spectrum Yellow™、Tweed Argyle 和 Spectrum Red™）在 12 种药物转运体中的 DDI 潜力，这些产品含有不同浓度的大麻二酚（CBD）和Δ-四氢大麻酚（Δ-THC）。使用表达人 ABC 转运体（ABCB1、ABCC2、ABCG2 或 ABCB11）和 SLC 转运体（SLC22A1、SLC22A2、SLC22A6、SLC22A8、SLCO1B1、SLCO1B3、SLC47A1 和 SLC47A2）的 HEK293 细胞或囊泡来测量转运体功能。 Spectrum Yellow 和 Tweed Argyle 抑制了 ABCG2 转运体的功能。基于 CBD 和 Δ-THC 含量，Spectrum Yellow 的 IC 值为 CBD 为 4.5 μM，Δ-THC 为 0.20 μM，Tweed Argyle 的 IC 值为 CBD 为 9.3 μM，Δ-THC 为 6.0 μM。Tweed Argyle 还抑制了 ABCB11 转运体的功能，CBD 和 Δ-THC 的 IC 值分别为 11.9 μM 和 7.7 μM。SLC22A6、SLC22A1、SLC22A2、SLCO1B1 和 SLCO1B3 转运体的功能被这些大麻类产品的高浓度适度抑制。三种大麻类产品均不抑制 ABCB1、ABCC2、SLC47A1、SLC47A2 或 SLC22A8 转运体。 新的发现是，大麻类产品抑制了 ABCB11、SLC22A6、SLC22A1、SLC22A2、SLCO1B1 和 SLCO1B3（尽管在大多数情况下都很温和）。Spectrum Yellow 和 Tweed Argyle 强力抑制了 ABCG2，未来的 DDI 研究可以评估大麻产品是否会影响 ABCG2 底物药物的药代动力学。
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