Lee Choong Whan, You Byoung Hoon, Yim Sreymom, Han Seung Yon, Chae Hee-Sung, Bae Mingoo, Kim Seo-Yeon, Yu Jeong-Eun, Jung Jieun, Nhoek Piseth, Kim Hojun, Choi Han Seok, Chin Young-Won, Kim Hyun Woo, Choi Young Hee
College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, Goyang-si, Gyeonggi-do, Republic of Korea.
National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, United States.
Front Pharmacol. 2023 Mar 10;14:1148155. doi: 10.3389/fphar.2023.1148155. eCollection 2023.
Metformin as an oral glucose-lowering drug is used to treat type 2 diabetic mellitus. Considering the relatively high incidence of cardiovascular complications and other metabolic diseases in diabetic mellitus patients, a combination of metformin plus herbal supplements is a preferrable way to improve the therapeutic outcomes of metformin. Ginseng berry, the fruit of Meyer, has investigated as a candidate in metformin combination mainly due to its anti-hyperglycemic, anti-hyperlipidemic, anti-obesity, anti-hepatic steatosis and anti-inflammatory effects. Moreover, the pharmacokinetic interaction of metformin OCTs and MATEs leads to changes in the efficacy and/or toxicity of metformin. Thus, we assessed how ginseng berry extract (GB) affects metformin pharmacokinetics in mice, specially focusing on the effect of the treatment period (i.e., 1-day and 28-day) of GB on metformin pharmacokinetics. In 1-day and 28-day co-treatment of metformin and GB, GB did not affect renal excretion as a main elimination route of metformin and GB therefore did not change the systemic exposure of metformin. Interestingly, 28-day co-treatment of GB increased metformin concentration in the livers (i.e., 37.3, 59.3% and 60.9% increases 1-day metformin, 1-day metformin plus GB and 28-day metformin groups, respectively). This was probably due to the increased metformin uptake OCT1 and decreased metformin biliary excretion MATE1 in the livers. These results suggest that co-treatment of GB for 28 days (i.e., long-term combined treatment of GB) enhanced metformin concentration in the liver as a pharmacological target tissue of metformin. However, GB showed a negligible impact on the systemic exposure of metformin in relation to its toxicity (i.e., renal and plasma concentrations of metformin).
二甲双胍作为一种口服降糖药物，用于治疗2型糖尿病。考虑到糖尿病患者心血管并发症和其他代谢疾病的发病率相对较高，二甲双胍与草药补充剂联合使用是提高二甲双胍治疗效果的一种较好方法。人参果，即迈耶人参的果实，已被研究作为二甲双胍联合用药的候选药物，主要是因为其具有降血糖、降血脂、抗肥胖、抗肝脂肪变性和抗炎作用。此外，二甲双胍与有机阳离子转运体（OCTs）和多药及毒素排出蛋白（MATEs）之间的药代动力学相互作用会导致二甲双胍的疗效和/或毒性发生变化。因此，我们评估了人参果提取物（GB）如何影响小鼠体内二甲双胍的药代动力学，特别关注GB的治疗期（即1天和28天）对二甲双胍药代动力学的影响。在二甲双胍和GB联合治疗1天和28天的实验中，GB不影响作为二甲双胍主要消除途径的肾脏排泄，因此GB不会改变二甲双胍的全身暴露量。有趣的是，GB联合治疗28天可增加肝脏中二甲双胍的浓度（即分别使1天二甲双胍组、1天二甲双胍加GB组和28天二甲双胍组的浓度增加37.3%、59.3%和60.9%）。这可能是由于肝脏中有机阳离子转运体1（OCT1）介导的二甲双胍摄取增加以及多药及毒素排出蛋白1（MATE1）介导的二甲双胍胆汁排泄减少所致。这些结果表明，GB联合治疗28天（即GB长期联合治疗）可提高肝脏中二甲双胍的浓度，而肝脏是二甲双胍的药理靶组织。然而，GB对二甲双胍全身暴露量及其毒性（即二甲双胍的肾脏和血浆浓度）的影响可忽略不计。
