Change of metformin concentrations in the liver as a pharmacological target site of metformin after long-term combined treatment with ginseng berry extract

Choong Whan Lee; Byoung Hoon You; Sreymom Yim; Seung Yon Han; Hee-Sung Chae; Mingoo Bae; Seo-Yeon Kim; Jeong-Eun Yu; Jieun Jung; Piseth Nhoek; Hojun Kim; Han Seok Choi; Young-Won Chin; Hyun Woo Kim; Young Hee Choi

doi:10.3389/fphar.2023.1148155

Change of metformin concentrations in the liver as a pharmacological target site of metformin after long-term combined treatment with ginseng berry extract

Front Pharmacol. 2023 Mar 10:14:1148155. doi: 10.3389/fphar.2023.1148155. eCollection 2023.

Authors

Affiliations

¹ College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, Goyang-si, Gyeonggi-do, Republic of Korea.
² National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, United States.
³ Department of Rehabilitation Medicine of Korean Medicine, Dongguk-University Ilsan Oriental Hospital, Goyang-si, Gyeonggi-do, Republic of Korea.
⁴ Division of Endocrinology and Metabolism, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi-do, Republic of Korea.
⁵ College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

Abstract

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 Panax ginseng 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 via 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 versus 1-day metformin, 1-day metformin plus GB and 28-day metformin groups, respectively). This was probably due to the increased metformin uptake via OCT1 and decreased metformin biliary excretion via 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).

Keywords: ginseng berry extract; metformin; multidrug and toxin extrusions; organic cation trans porters; pharmacokinetics; tissue distribution.

Grants and funding

This research was funded by National Research Foundation of Korea grant (MSIT) (NRF-2018R1A5A2023127, NRF-2016R1C1B2010849 and NRF-2021R1A2C1094462) (YC).