임상약리학회지 (Journal of Korean Society for Clinical Pharmacology and Therapeutics)

대한임상약리학회 (Korean Society for Clinical Pharmacology and Therapeutics)
권호 표지

건강한 한국인 자원자에서 메트포민의 Targeted Metabolite Profiling

Targeted Plasma Metabolite Profiling of Metformin in Healthy Korean Volunteers

  • 임호섭 (고신대학교 의과대학 가정의학과교실) ;
  • 차재민 (경북대학교 대학원 의과학과) ;
  • 서정주 (경북대학교 대학원 의과학과) ;
  • 박정현 (경북대학교 대학원 의과학과) ;
  • 이주미 (경북대학교 대학원 의과학과) ;
  • 이혜원 (경북대학교병원 임상시험센터) ;
  • 배균섭 (서울아산병원 임상약리학과) ;
  • 김우미 (고신대학교 의과대학 약리학교실) ;
  • 윤영란 (경북대학교 대학원 의과학과)
  • Lihm, Ho-Seob (Department of Family Medicine, Kosin University College of Medicine) ;
  • Cha, Jaemin (Department of Biomedical Science, Kyungpook National University Graduate School) ;
  • Seo, Jeong Ju (Department of Biomedical Science, Kyungpook National University Graduate School) ;
  • Park, Jeonghyeon (Department of Biomedical Science, Kyungpook National University Graduate School) ;
  • Lee, Joomi (Department of Biomedical Science, Kyungpook National University Graduate School) ;
  • Lee, Hae Won (Clinical Trial Center, Kyungpook National University Hospital) ;
  • Bae, Kyun Seop (Department of Clinical Pharmacology & Therapeutics, Asan Medical Center) ;
  • Kim, Woomi (Department of Pharmacology, Kosin University College of Medicine) ;
  • Yoon, Young-Ran (Department of Biomedical Science, Kyungpook National University Graduate School)
  • 투고 : 2012.11.20
  • 심사 : 2012.12.15
  • 발행 : 2012.12.31
⟨ 이전 논문 다음 논문 ⟩

초록

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.

키워드

참고문헌

  1. United Kingdom Prospective Diabetes Study (UKPDS). Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ, 1995;310(6972):83-88. https://doi.org/10.1136/bmj.310.6972.83
  2. United Kingdom Prospective Diabetes Study (UKPDS). A randomized trial of efficacy of early addition of metformin in sulfonylureatreated type 2 diabetes. Diabetes Care, 1998; 21(1):87-92. https://doi.org/10.2337/diacare.21.1.87
  3. Glueck CJ, Fontaine RN, Wang P, Subbiah MT, Weber K, Illig E, Streicher P, Sieve-Smith L, Tracy TM, Lang JE, McCullough P. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism, 2001; 50(7):856-861. https://doi.org/10.1053/meta.2001.24192
  4. United Kingdom Prospective Diabetes Study (UKPDS). Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet, 1998;352(9131):854-865. https://doi.org/10.1016/S0140-6736(98)07037-8
  5. Liu F, Lu JX, Tang JL, Li L, Lu HJ, Hou XH, Jia WP, Xiang KS. Relationship of plasma creatinine and lactic acid in type 2 diabetic patients without renal dysfunction. Chin Med J (Engl), 2009;122(21):2547-2553.
  6. Tahrani AA, Varughese GI, Scarpello JH, Hanna FW. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ, 2007;335(7618):508-512. https://doi.org/10.1136/bmj.39255.669444.AE
  7. Jeong BC. Metabolomics in disease researches. Molecular and Cellular Biology News. 2006;3: 17-27. (Korean)
  8. Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM. Clinical pharmacokinetics of metformin. Clin Pharmacokinet, 2011;50(2):81-98 https://doi.org/10.2165/11534750-000000000-00000
  9. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care, 2011;34(6): 1431-1437. https://doi.org/10.2337/dc10-2361
  10. Kruse JA. Metformin-associated lactic acidosis. J Emerg Med. 2001;20(3):267-272. https://doi.org/10.1016/S0736-4679(00)00320-6
  11. Stades AM, Heikens JT, Erkelens DW, Holleman F, Hoekstra JB. Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med, 2004;255(2): 179-187. https://doi.org/10.1046/j.1365-2796.2003.01271.x
  12. Chui W. Metformin and contrast media. The Hongkong Medical Diary, 2006;11(6):19-20.
  13. Marchetti P, Masiello P, Benzi L, Cecchetti P, Fierabracci V, Giannarelli R, Gregorio F, Brunetti P, Navalesi R. Effects of metformin therapy on plasma amino acid pattern in patients with maturity-onset diabetes. Drugs Exp Clin Res, 1989;15(11-12):565-570.
  14. Johnson AB, Webster JM, Sum CF, Heseltine L, Argyraki M, Cooper BG, Taylor R. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetes patients. Metabolism, 1993;42(9): 1217-1222. https://doi.org/10.1016/0026-0495(93)90284-U
  15. Cai S, Huo T, Li N, Xiong Z, Li F. Lysophosphatidylcholine- biomarker of metformin action: studied using UPLC/MS/MS. Biomed Chromatogr, 2009;23(7):782-786. https://doi.org/10.1002/bmc.1185