pharmaceutics-11-00189

Abstract

  • The study investigates the herb–drug interactions between Red Ginseng Extract (RGE) and Metformin in rats.

  • Focus is on modulation of metformin transporters: Organic Cation Transporter (Oct), Multiple Toxin and Extrusion Protein (Mate), and Plasma Membrane Monoamine Transporter (Pmat).

  • Single RGE administration does not impact transport activity over 500 µg/mL.

  • Repeated RGE administration increases intestinal Oct1 mRNA while decreasing hepatic Oct1.

  • Intestinal permeability of metformin increased, but 3-O-methyl-D-glucose and Lucifer yellow permeability remained unchanged, indicating substrate specificity.

  • Repeated doses significantly increased plasma concentrations of metformin, enhancing absorption.

  • Conclusion: RGE shows a pharmacokinetic interaction that merits further therapeutic evaluation.

Introduction

  • Diabetes mellitus poses significant health threats globally with rising numbers of patients.

  • Effective glycemic control is crucial, thus add-on therapy with drugs differing in action, such as Metformin, is common.

  • Metformin removal is primarily renal, involving transporters like OCT2 and MATE1/2 for active excretion.

  • Metformin's absorption predominantly occurs in the intestine (20% in duodenum, 60% in jejunum/ileum).

  • Korean Red Ginseng reportedly improves diabetic conditions due to its hypoglycemic effects via pathways involving AMPK.

Materials and Methods

2.1 Materials

  • Red Ginseng Extract obtained from Punggi Cooperative Association.

  • Metformin, cimetidine, 3-O-methyl-D-glucose, and Lucifer yellow purchased from Sigma-Aldrich.

2.2 Transport Activity Measurement

  • HEK293 cells overexpressing relevant transporters used to investigate inhibitory effects of RGE on transporter-mediated metformin uptake.

  • Incubation with [14C]metformin, assessing uptake in response to RGE and cimetidine over different concentrations.

2.3 Animal Studies

  • Male Sprague-Dawley rats (control, single, repeated treatment groups) were used for in vivo studies.

  • Treatment included combinations of water and RGE.

2.4 Ginsenosides Analysis

  • Ginsenosides levels measured via LC–MS/MS in RGE and plasma samples post-treatment.

2.5 mRNA and Protein Analysis

  • mRNA levels of Oct1, Oct2, Mate1, and Pmat assessed using qRT-PCR.

  • Western blot analysis performed to evaluate protein expression.

2.6 Intestinal Permeability Assessment

  • Permeability studies conducted using isolated intestinal segments mounted on Ussing chambers, measuring metformin absorption.

2.7 Pharmacokinetics of Metformin

  • Upon single or repeated RGE treatment, rats received metformin intravenously and orally while monitoring urine output.

2.8 LC-MS/MS Analysis

  • Pharmacokinetics assessed using a specific LC-MS/MS method adapted for metformin measurement.

2.9 Data Analysis

  • Statistical methods applied using SPSS, evaluating transport rates and pharmacokinetic parameters based on established models.

Results

3.1 Ginsenoside Concentration

  • Analyses confirm ginsenosides in RGE effective for diabetic treatment.

3.2 Inhibitory Effects of RGE

  • RGE shows no significant inhibition on OCT1 and OCT2 but affects MATE1 and MATE2-K at higher concentrations.

3.3 mRNA and Protein Expression Changes

  • 1-week RGE treatment affects Oct1 mRNA levels in the intestine and liver, contrasting with Oct2, Mate1, and Pmat.

  • Protein analysis reveals increased Oct1 in enterocytes but decreased in liver.

3.4 Metformin Permeability

  • Repeated RGE treatment enhances metformin absorption significantly in the duodenum and ileum with unchanged permeability for glucose and Lucifer yellow.

3.5 Pharmacokinetics Analysis

  • Intravenous Administration: Metformin pharmacokinetics remain unchanged with RGE treatment.

  • Oral Administration: Increased T1/2, Cmax, AUC, and urinary excretion of metformin in the 1WRA group.

Discussion

  • The study provides insights into how RGE affects the pharmacokinetics of metformin through modulation of transporters.

  • Further investigation is recommended considering the clinical implications of RGE on therapy involving metformin.