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

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.

FIGURE 1

.Metformin uptake in HEK293 cells overexpressing (A) hOCT1, (B) hOCT2, (C) hMATE1, and (D) hMATE2-K. Cimetidine at 100, 100, 1 and 10 μM was used as a well-known of OCT1, OCT2, MATE1 and MATE2-K, respectively. ^aMC group was significantly different (p < 0.05) from other groups. ^bMGB500 and MC groups were significantly different (p < 0.05) from M and MGB5 groups. ^cMGB500 and MC groups were significantly different (p < 0.05) from M and MGB5 groups, and also there was a significant difference (p < 0.05) between MC and MGB500 groups.

FIGURE 2

The mean plasma concentration-time profiles of metformin after oral administration of metformin with (●; 1 MGB and 28 MGB) and without GB (○; 1 M and 28 M) to mice, respectively. The doses of metformin and GB were 50 and 200 mg/kg, respectively. Treatment periods were 1-day (A) and consecutive 28-day (B), respectively.

FIGURE 3

Relative mRNA expressions of OCT1, OCT2, MATE1 and MATE2-K in (A) livers and (B) kidneys of control, 1 M, 1 MGB, 28 M and 28 MGB groups, respectively. ^a28 MGB was significantly different (p < 0.05) from other groups.