Targeted Plasma Metabolite Profiling of Metformin in Healthy Korean Volunteers

Ho-Seob Lihm; Jaemin Cha; Jeong Ju Seo; Jeonghyeon Park; Joomi Lee; Hae Won Lee; Kyun Seop Bae; Woomi Kim; Young-Ran Yoon

doi:10.0000/jkscpt.2012.20.2.175

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Lihm, Cha, Seo, Park, Lee, Lee, Bae, Kim, and Yoon: Targeted Plasma Metabolite Profiling of Metformin in Healthy Korean Volunteers

Original Article

Journal of Korean Society for Clinical Pharmacology and Therapeutics

Journal of Korean Society for Clinical Pharmacology and Therapeutics 2012; 20(2): 175-181.

Published online: 31 December 2012

DOI: https://doi.org/10.0000/jkscpt.2012.20.2.175

Targeted Plasma Metabolite Profiling of Metformin in Healthy Korean Volunteers

Ho-Seob Lihm^1,^†, Jaemin Cha^2,^3,^†, Jeong Ju Seo^2,³, Jeonghyeon Park^2,³, Joomi Lee^2,³, Hae Won Lee³, Kyun Seop Bae⁴, Woomi Kim⁵, Young-Ran Yoon^2,³

¹Department of Family Medicine, Kosin University College of Medicine, Busan, Korea.

²Department of Biomedical Science, Kyungpook National University Graduate School, Daegu, Korea.

³Clinical Trial Center, Kyungpook National University Hospital, Daegu, Korea.

⁴Department of Clinical Pharmacology & Therapeutics, Asan Medical Center, Seoul, Korea.

⁵Department of Pharmacology, Kosin University College of Medicine, Busan, Korea.

Corresponding author (yry@knu.ac.kr)

Equal contributor:

†These authors equally contributed to this work.

Received 20 November 2012 Revised 11 December 2012 Accepted 15 December 2012

Abstract

Background

Metformin is an effective oral antihyperglycaemic agent for type 2 diabetes mellitus, with a variety of metabolic effects. In addition to controlling blood glucose level, it has been appeared to decrease the long-period complications of diabetes, including macrovascular disease. Few reports have addressed the metabolite profiling of metformin. The study was to evaluate if targeted metabolic profiling approach is sensitive enough to predict the therapeutic effects of metformin after a single oral dose.

Methods

A randomized, open-label, single-dose study was conducted in twenty eight healthy Korean male volunteers. To determine the concentrations of endogenous metabolites in their pre-dose and post-dose plasma samples, blood samples were collected before and at 2 and 6 h after a single oral dose of 500 mg metformin. Both Modular P/Modular D analyzer and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based metabolic profiling was performed.

Results

We quantified pre-dose and post-dose creatinine, blood urea nitrogen (BUN), lactic acid, 7 amino acids (lysine, glutamic acid, alanine, valine, leucine, phenylalanine, tryptophan), and 5 lysophosphatidylcholines (14:0, 16:0, 17:0, 18:0, and 18:1) using autoanalyser and UPLC-MS/MS. The postdose levels of alanine, lactic acid, glutamic acid, lysine, valine, leucine, phenylalanine, tryptophan, and lysoPC (18:1) were slightly decreased with statistical significance, but there is no clinical significance.

Conclusion

In order to explore the potential endogenous metabolites associated with the therapeutic effects of metformin, further study including non-targeted (global) metabolite profiling is needed.

Keywords: Metformin, Targeted metabolite profiling, UPLC-MS/MS

Figures and Tables

Figure 1

Chemical structure of metformin.

Figure 2

Comparison of targeted metabolite concentrations at 0 (predose), 2h and 6h after a single 500-mg oral dose of metformin. Boxes indicate interquantile range and whisker bars indicate 10th and 90th percentiles. Horizontal bars located in the middle of the boxes represent the median values. ^*P-value < 0.05, compared between baseline (predose) and 2h or 6h values by repeated measures ANOVA test.

Table 1

Analytical method for UPLC-MS/MS

^*A buffer: 0.1% formic acid in DW; B buffer: 0.1% formic acid in acetonitrile.

Table 2

Analytical condition of the MRM transition of UPLC-MS/MS

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