Department of Neurology, Oregon Health and Science University, Portland, Oregon (K.M.W., J.F.Q., A.S.); Departments of Chemistry (A.A.M., C.S.M.) and Pharmaceutical Sciences (J.F.S.) and Linus Pauling Institute (A.A.M., J.F.S.), Oregon State University, Corvallis, Oregon; BioIVT, Durham, North Carolina (R.M.L., C.L.M., T.T.B.); and Department of Neurology, Veterans Affairs Portland Health Care System Center, Portland, Oregon (J.F.Q.).
Department of Neurology, Oregon Health and Science University, Portland, Oregon (K.M.W., J.F.Q., A.S.); Departments of Chemistry (A.A.M., C.S.M.) and Pharmaceutical Sciences (J.F.S.) and Linus Pauling Institute (A.A.M., J.F.S.), Oregon State University, Corvallis, Oregon; BioIVT, Durham, North Carolina (R.M.L., C.L.M., T.T.B.); and Department of Neurology, Veterans Affairs Portland Health Care System Center, Portland, Oregon (J.F.Q.)
Drug Metab Dispos. 2020 Oct;48(10):1053-1063. doi: 10.1124/dmd.120.090860. Epub 2020 Jun 24.
(CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside and their corresponding aglycones asiatic acid and madecassic acid. Exploration of the bioactivity of CA's caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P450 enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter-certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7 µg/ml CAW-R61J (equivalent to 1.1 µM asiaticoside, 0.8 µM madecassoside, 0.09 µM asiatic acid, and 0.12 µM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 were evaluated using human liver microsomes. CAW-R61J showed weak reversible inhibition of most of the P450 forms tested, with the strongest being CYP2C9 (IC of 330 µg/ml). CAW-R61J (≤1000 µg/ml) was not a time-dependent inhibitor of any of these P450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P450 induction and inhibition in vitro. The clinical relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrations measured in our recent clinical studies suggest minimal risk of P450-mediated drug interactions by these components. SIGNIFICANCE STATEMENT: A preparation of is currently under clinical development for the prevention or treatment of cognitive decline. The US Food and Drug Administration required an evaluation of its potential for drug interactions mediated through drug-metabolizing enzymes. This in vitro study revealed minimal induction or inhibition of a range of P450 enzymes, including CYP3A4, by the extract, suggesting a low potential for drug interactions modulated by P450 metabolism.
（CA）在治疗认知能力下降方面具有作为植物药的巨大潜力。其主要生物活性成分包括三萜糖苷化合物积雪草苷和羟基积雪草苷及其相应的苷元积雪草酸和羟基积雪草酸。目前正在探索 CA 中咖啡酰奎宁酸的生物活性。在这项研究中，根据美国食品和药物管理局的要求，通过对 P450 酶的抑制或诱导作用，评估 CA 的水提物（CAW-R61J）的药物相互作用潜力。使用经过运输蛋白认证的冷冻保存人肝细胞在三明治培养物中评估 CAW-R61J 对 CYP1A2、CYP2B6 和 CYP3A4 的诱导潜力。定量检测这些靶 P450 的基因表达，并确定酶活性以确认基因表达结果。在高达 16.7µg/ml CAW-R61J（相当于 1.1µM 积雪草苷、0.8µM 羟基积雪草苷、0.09µM 积雪草酸和 0.12µM 羟基积雪草酸）的浓度下未观察到诱导作用。使用人肝微粒体评估 CAW-R61J 对 CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6 和 CYP3A4/5 的可逆和时间依赖性抑制作用。CAW-R61J 对所测试的大多数 P450 形式表现出较弱的可逆抑制作用，对 CYP2C9 的抑制作用最强（IC 为 330µg/ml）。CAW-R61J（≤1000µg/ml）对这些 P450 酶均无时间依赖性抑制作用。总之，CAW-R61J 对体外的 P450 诱导和抑制作用没有影响，或者只有微弱影响。这些结果的临床相关性将取决于人类体内达到的 CAW-R61J 成分的浓度。我们最近的临床研究中测量的血浆三萜浓度表明，这些成分引起 P450 介导的药物相互作用的风险很小。
声明：一种名为 的制剂目前正在临床开发中，用于预防或治疗认知能力下降。美国食品和药物管理局要求对其通过代谢酶介导的药物相互作用的潜力进行评估。这项体外研究表明，该提取物对一系列 P450 酶（包括 CYP3A4）的诱导或抑制作用极小，表明其通过 P450 代谢调节药物相互作用的潜力较低。
