Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice.
Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice.
复制标题
DOI：
10.1124/dmd.123.001360
复制
发表时间：
2023-11
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
毛茛是原产于北美东部的多年生植物。最近的一项临床研究报告称，goldenseal使二甲双胍Cmax和血药浓度-时间曲线下面积（AUC）分别降低27%和23%，但半衰期和肾脏清除率不变。这些观察结果表明，毛茛改变了二甲双胍吸收过程。潜在机制仍未知。二甲双胍全身暴露量降低的一种机制是黄毛菊抑制参与二甲双胍吸收的肠道摄取转运蛋白。使用过表达有机阳离子转运体（OCT）3、质膜单胺转运体（PMAT）和硫胺素转运体（THTR）2的人胚肾293细胞，测试了毛茛提取物和三种毛茛生物碱（小檗碱、（-）-β-海金沙碱、海金沙碱）作为有机阳离子转运体（OCT）3、质膜单胺转运体（PMAT）和硫胺素转运体（THTR）2的抑制剂。以小檗碱含量标准化的白毛茛提取物是每种转运蛋白的最强抑制剂（OCT 3、PMAT和THTR 2的IC 50分别为4.9、13.1和5.8 μM）。在小鼠中进行的药代动力学研究比较了小檗碱、（-）-β-海斯汀、毛茛提取物和伊马替尼（OCT抑制剂）对口服二甲双胍的影响。毛茛提取物和伊马替尼分别使二甲双胍Cmax显著降低31%和25%，对半衰期无影响。小檗碱和（-）-β-海斯汀对二甲双胍的药代动力学没有影响，表明两种生物碱单独在体内都不会引起相互作用。一项涉及静脉注射二甲双胍和口服抑制剂的后续小鼠研究检查了基底外侧肠/肝摄取转运蛋白对金线莲-二甲双胍相互作用的贡献。毛茛提取物和伊马替尼对二甲双胍AUC和半衰期没有影响，表明对基底外侧肠/肝摄取转运蛋白缺乏抑制作用。这些结果可能对服用白毛茛的患者产生影响，因为这些药物是OCT 3和THTR 2的底物。毛茛被用来自我治疗呼吸道感染和消化系统疾病。我们研究了在goldenseal和二甲双胍之间观察到的临床药代动力学相互作用的潜在机制，特别是goldenseal对二甲双胍吸收相关的肠道摄取转运蛋白（OCT 3、PMAT、THTR 2）的抑制。毛茛提取物在体外抑制所有三种转运蛋白，并降低小鼠二甲双胍的全身暴露量。这些数据可能对同时服用毛茛和其他药物的患者有更广泛的影响，这些药物是这些转运蛋白的底物。
Goldenseal is a perennial plant native to eastern North America. A recent clinical study reported goldenseal decreased metformin Cmax and area under the blood concentration versus time curve (AUC) by 27% and 23%, respectively, but half-life and renal clearance were unchanged. These observations suggested goldenseal altered processes involved in metformin absorption. The underlying mechanism(s) remain(s) unknown. One mechanism for the decreased metformin systemic exposure is inhibition by goldenseal of intestinal uptake transporters involved in metformin absorption. Goldenseal extract and three goldenseal alkaloids (berberine, (–)-β-hydrastine, hydrastinine) were tested as inhibitors of organic cation transporter (OCT) 3, plasma membrane monoamine transporter (PMAT), and thiamine transporter (THTR) 2 using human embryonic kidney 293 cells overexpressing each transporter. The goldenseal extract, normalized to berberine content, was the strongest inhibitor of each transporter (IC50: 4.9, 13.1, and 5.8 μM for OCT3, PMAT, and THTR2, respectively). A pharmacokinetic study in mice compared the effects of berberine, (–)-β-hydrastine, goldenseal extract, and imatinib (OCT inhibitor) on orally administered metformin. Goldenseal extract and imatinib significantly decreased metformin Cmax by 31% and 25%, respectively, and had no effect on half-life. Berberine and (–)-β-hydrastine had no effect on metformin pharmacokinetics, indicating neither alkaloid alone precipitated the interaction in vivo. A follow-up murine study involving intravenous metformin and oral inhibitors examined the contributions of basolateral enteric/hepatic uptake transporters to the goldenseal–metformin interaction. Goldenseal extract and imatinib had no effect on metformin AUC and half-life, suggesting lack of inhibition of basolateral enteric/hepatic uptake transporters. Results may have implications for patients taking goldenseal with drugs that are substrates for OCT3 and THTR2. Goldenseal is used to self-treat respiratory infections and digestive disorders. We investigated potential mechanisms for the clinical pharmacokinetic interaction observed between goldenseal and metformin, specifically inhibition by goldenseal of intestinal uptake transporters (OCT3, PMAT, THTR2) involved in metformin absorption. Goldenseal extract inhibited all three transporters in vitro and decreased metformin systemic exposure in mice. These data may have broader implications for patients co-consuming goldenseal with other drugs that are substrates for these transporters.
登录
查看更多内容
影响因子：
5.6
作者：
Floerl S;Kuehne A;Hagos Y
通讯作者：
Hagos Y
影响因子：
3.2
作者：
Padmanabhan P;Grosse J;Asad AB;Radda GK;Golay X
通讯作者：
Golay X
影响因子：
21.1
作者：
Liang, Yu;Li, Siqi;Chen, Ligong
通讯作者：
Chen, Ligong
影响因子：
3.9
作者：
Gupta, Prem K.;Barone, Gary;Hendrickson, Howard P.
通讯作者：
Hendrickson, Howard P.
影响因子：
5.8
作者：
Müller, J;Lips, KS;Brandsch, M
通讯作者：
Brandsch, M