Jin Sojeong, Lee Sowon, Jeon Ji-Hyeon, Kim Hyuna, Choi Min-Koo, Song Im-Sook
College of Pharmacy, Dankook University, Cheon-an 31116, Korea.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
Pharmaceutics. 2019 Apr 18;11(4):189. doi: 10.3390/pharmaceutics11040189.
We aimed to assess the potential herb-drug interactions between Korean red ginseng extract (RGE) and metformin in rats in terms of the modulation of metformin transporters, such as organic cation transporter (Oct), multiple toxin and extrusion protein (Mate), and plasma membrane monoamine transporter (Pmat). Single treatment of RGE did not inhibit the in vitro transport activity of OCT1/2 up to 500 µg/mL and inhibited MATE1/2-K with high IC value (more than 147.8 µg/mL), suggesting that concomitant used of RGE did not directly inhibit OCT- and MATE-mediated metformin uptake. However, 1-week repeated administration of RGE (1.5 g/kg/day) (1WRA) to rats showed different alterations in mRNA levels of Oct1 depending on the tissue type. RGE increased intestinal Oct1 but decreased hepatic Oct1. However, neither renal Oct1/Oct2 nor Mate1/Pmat expression in duodenum, jejunum, ileum, liver, and kidney were changed in 1WRA rats. RGE repeated dose also increased the intestinal permeability of metformin; however, the permeability of 3--methyl-d-glucose and Lucifer yellow was not changed in 1WRA rats, suggesting that the increased permeability of metformin by multiple doses of RGE is substrate-specific. On pharmacokinetic analysis, plasma metformin concentrations following intravenous injection were not changed in 1WRA, consistent with no significant change in renal Oct1, Oct2, and mate1. Repeated doses of RGE for 1 week significantly increased the plasma concentration of metformin, with increased half-life and urinary excretion of metformin following oral administration of metformin (50 mg/kg), which could be attributed to the increased absorption of metformin. In conclusion, repeated administration of RGE showed in vivo pharmacokinetic herb-drug interaction with metformin, with regard to its plasma exposure and increased absorption in rats. These results were consistent with increased intestinal Oct1 and its functional consequence, therefore, the combined therapeutic efficacy needs further evaluation before the combination and repeated administration of RGE and metformin, an Oct1 substrate drug.
我们旨在通过调节二甲双胍转运蛋白，如有机阳离子转运体（Oct）、多重毒素和外排蛋白（Mate）以及质膜单胺转运体（Pmat），评估大鼠体内韩国红参提取物（RGE）与二甲双胍之间潜在的草药-药物相互作用。单独给予RGE高达500μg/mL时，并未抑制OCT1/2的体外转运活性，且对MATE1/2-K的抑制作用IC值较高（超过147.8μg/mL），这表明同时使用RGE不会直接抑制OCT和MATE介导的二甲双胍摄取。然而，对大鼠连续1周重复给予RGE（1.5g/kg/天）（1WRA）后，根据组织类型不同，Oct1的mRNA水平出现了不同变化。RGE使肠道Oct1增加，但使肝脏Oct1减少。然而，在1WRA大鼠中，十二指肠、空肠、回肠、肝脏和肾脏中的肾Oct1/Oct2以及Mate1/Pmat表达均未改变。RGE重复给药也增加了二甲双胍的肠道通透性；然而，1WRA大鼠中3-甲基-D-葡萄糖和荧光素黄的通透性未改变，这表明多剂量RGE导致的二甲双胍通透性增加具有底物特异性。药代动力学分析表明，静脉注射后1WRA大鼠血浆中的二甲双胍浓度未改变，这与肾Oct1、Oct2和mate1无显著变化一致。连续1周重复给予RGE后，口服二甲双胍（50mg/kg）后，二甲双胍的血浆浓度显著增加，半衰期延长，尿排泄增加，这可能归因于二甲双胍吸收增加。总之，重复给予RGE在大鼠体内显示出与二甲双胍的药代动力学草药-药物相互作用，涉及血浆暴露和吸收增加。这些结果与肠道Oct1增加及其功能结果一致；因此，在联合使用并重复给予RGE和作为Oct1底物药物的二甲双胍之前，需要进一步评估联合治疗效果。
