Journal of Natural Medicines ( IF 2.5 ) Pub Date : 2021-07-25 , DOI: 10.1007/s11418-021-01552-8 Akiko Nakayama 1 , Kazuaki Tsuchiya 1 , Lingyu Xu 2 , Takashi Matsumoto 1 , Toshiaki Makino 2
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Paclitaxel, a standard chemotherapeutic agent for several types of cancer, including ovarian, breast, and non-small-cell lung cancer, causes peripheral neuropathy as an adverse effect in 60–70% of the patients. The utility of combination therapy with paclitaxel and goshajinkigan, a traditional Japanese Kampo medicine, in managing paclitaxel-induced neuropathy during chemotherapy has been explored. Paclitaxel is predominantly metabolized in the liver by cytochrome P450 (CYP) 2C8 to produce 6α-hydroxypaclitaxel and by CYP3A4 to produce 3′-p-hydroxypaclitaxel. In this study, we evaluated the inhibitory or inducing effects of goshajinkigan extract (GJG) and its representative and bioavailable constituents, geniposidic acid, plantagoguanidinic acid, paeoniflorin, catalpol, loganin, and neoline, on the metabolism of paclitaxel via CYP2C8 and CYP3A4 using pooled human liver microsomes and cultured human cryopreserved hepatocytes to provide the drug information about the pharmacokinetic interaction of this combination therapy. GJG significantly inhibited the production of 3’-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel in vitro in a concentration-dependent manner. The half maximal inhibitory concentration (IC50) values of GJG were 4.5 and 7.8 mg/ml, respectively, for 3′-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel productions. Neoline inhibited the production of 3′-p-hydroxypaclitaxel at 50 μM, but not at lower concentrations. Apart from neoline, other GJG constituents (at concentrations up to 50 or 10 μM of all test substances) did not exhibit inhibitory or inducing effects. Since GJG showed the inhibitory effect on the metabolism of paclitaxel at much higher concentrations than those used clinically, it can be concluded that GJG product does not exhibit any pharmacokinetic interaction with paclitaxel in clinical practice.
Graphic abstract
中文翻译：
紫杉醇与合药丸提取物及其成分的药物相互作用
紫杉醇是多种癌症（包括卵巢癌、乳腺癌和非小细胞肺癌）的标准化疗药物，会导致 60-70% 的患者出现周围神经病变作为不良反应。已经探索了紫杉醇与日本传统汉方药 goshajinkigan 联合治疗在控制化疗期间紫杉醇引起的神经病变中的效用。紫杉醇在肝脏中主要通过细胞色素 P450 (CYP) 2C8 代谢产生 6α-羟基紫杉醇，并通过 CYP3A4 代谢产生 3'-对羟基紫杉醇。在这项研究中，我们评估了 goshajinkigan 提取物 (GJG) 及其代表性和生物可利用成分、栀子苷酸、车前子胍酸、芍药甙、梓醇、马钱甙和 neoline 的抑制或诱导作用，通过 CYP2C8 和 CYP3A4 通过 CYP2C8 和 CYP3A4 代谢紫杉醇，使用汇集的人肝微粒体和培养的人冷冻保存肝细胞，以提供有关这种联合疗法的药代动力学相互作用的药物信息。GJG 在体外以浓度依赖性方式显着抑制 3'-p-羟基紫杉醇和 6α-羟基紫杉醇的产生。半数抑制浓度（IC50 ) 对于 3'-p-羟基紫杉醇和 6α-羟基紫杉醇的生产，GJG 的值分别为 4.5 和 7.8 mg/ml。Neoline 在 50 μM 时抑制 3'-p-羟基紫杉醇的产生，但在较低浓度时则不会。除了 neoline，其他 GJG 成分（所有测试物质的浓度高达 50 或 10 μM）没有表现出抑制或诱导作用。由于 GJG 在比临床使用的浓度高得多的浓度下显示出对紫杉醇代谢的抑制作用，因此可以得出结论，GJG 产品在临床实践中与紫杉醇没有任何药代动力学相互作用。
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