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Toxicokinetics of metformin-associated lactic acidosis with continuous renal replacement therapy

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Abstract

A 70-year-old diabetic male patient with a baseline serum creatinine of 1.4 mg/dL presented with nausea and vomiting. He was diagnosed with metformin-associated lactic acidosis and acute kidney injury. He was managed with continuous veno-venous hemodiafiltration (CVVHDF). By measuring metformin concentration at different time intervals, we calculated the apparent volume of distribution of metformin at 34.7 L. The decline in serum metformin followed single-compartment first-order kinetics with an elimination rate constant of 0.0418/h and a serum half-life of 16.5 h; no metformin rebound was seen after discontinuation of CVVHDF. Using the previously calculated volume of distribution we calculated the expected serum metformin concentration 25 h post CVVHDF to be 3.0–3.7 μg/mL. The measured serum metformin of 3.4 μg/ml fell within the predicted range. During CVVHDF, dialyzer metformin clearance approximates 88.7 % of dialyzer urea clearance and 90.1 % of dialyzer creatinine clearance.

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References

  • Alivanis P, Giannikouris I et al (2006) Metformin-associated lactic acidosis treated with continuous renal replacement therapy. Clin Ther 28(3):396–400

    Article  PubMed  Google Scholar 

  • Almirall J, Briculle M et al (2008) Metformin-associated lactic acidosis in type 2 diabetes mellitus: incidence and presentation in common clinical practice. Nephrol Dial Transplant 23(7):2436–2438

    Article  PubMed  CAS  Google Scholar 

  • Bailey CJ, Turner RC (1996) Metformin. N Engl J Med 334(9):574–579

    Article  PubMed  CAS  Google Scholar 

  • Barrueto F, Meggs WJ et al (2002) Clearance of metformin by hemofiltration in overdose. J Toxicol Clin Toxicol 40(2):177–180

    Article  PubMed  Google Scholar 

  • Dunn CJ, Peters DH (1995) Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs 49(5):721–749

    Article  PubMed  CAS  Google Scholar 

  • UKPDS (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352(9131):854–865

    Google Scholar 

  • Emslie-Smith AM, Boyle DI, Evans JM, Sullivan F, Morris AD, DARTS/MEMO Collaboration (2001) Contraindications to metformin therapy in patients with type 2 diabetes—a population-based study of adherence to prescribing guidelines. Diabet Med 18(6):483–488

    Article  PubMed  CAS  Google Scholar 

  • Friesecke S, Abel P et al (2006) Combined renal replacement therapy for severe metformin-induced lactic acidosis. Nephrol Dial Transplant 21(7):2038–2039

    Article  PubMed  Google Scholar 

  • Guo PY, Storsley LJ et al (2006) Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial 19(1):80–83

    Article  PubMed  Google Scholar 

  • Holstein A, Nahrwold D et al (1999) Contra-indications to metformin therapy are largely disregarded. Diabet Med 16(8):692–696

    Article  PubMed  CAS  Google Scholar 

  • Lalau JD, Race JM (1999) Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 20(4):377–384

    Article  PubMed  CAS  Google Scholar 

  • Lalau JD, Andrejak M et al (1989) Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin: a study of metformin elimination. Int J Clin Pharmacol Ther Toxicol 27(6):285–288

    PubMed  CAS  Google Scholar 

  • Misbin RI, Green L et al (1998) Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 338(4):265–266

    Article  PubMed  CAS  Google Scholar 

  • Pearlman BL, Fenves AZ et al (1996) Metformin-associated lactic acidosis. Am J Med 101(1):109–110

    Article  PubMed  CAS  Google Scholar 

  • Pentikainen PJ, Neuvonen PJ et al (1979) Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol 16(3):195–202

    Article  PubMed  CAS  Google Scholar 

  • Salpeter SE, Greyber et al. (2006) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev (1):CD002967

  • Sambol NC, Chiang J et al (1995) Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol 35(11):1094–1102

    PubMed  CAS  Google Scholar 

  • Scheen AJ (1996) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 30(5):359–371

    Article  PubMed  CAS  Google Scholar 

  • Sirtori CR, Franceschini G et al (1978) Disposition of metformin (N, N-dimethylbiguanide) in man. Clin Pharmacol Ther 24(6):683–693

    PubMed  CAS  Google Scholar 

  • Stang M, Wysowski DK et al (1999) Incidence of lactic acidosis in metformin users. Diabetes Care 22(6):925–927

    Article  PubMed  CAS  Google Scholar 

  • Stumvoll M, Nurjhan N et al (1995) Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 333(9):550–554

    Article  PubMed  CAS  Google Scholar 

  • Wiholm BE, Myrhed M (1993) Metformin-associated lactic acidosis in Sweden 1977–1991. Eur J Clin Pharmacol 44(6):589–591

    Article  PubMed  CAS  Google Scholar 

  • Zhou G, Myers R et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108(8):1167–1174

    PubMed  CAS  Google Scholar 

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Conflict of interest

All authors have no conflict of interest to disclose.

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Authors and Affiliations

  1. Division of Nephrology and Transplant, Indiana University School of Medicine, Indianapolis, USA

    Muhammad Mujtaba

  2. Department of Medicine, Division of Nephrology, Columbia University Medical Center, 622W 168th Street, PH4-124, New York, NY, 10032, USA

    Abdallah Sassine Geara & Sumit Mohan

  3. Department of Medicine, University of Arizona College of Medicine, Tucson, Phoenix, AZ, USA

    Machaiah Madhrira

  4. Division of Nephrology, Harlem Hospital Center, Columbia University College of Physicians and Surgeons, New York, USA

    Rajesh Agarwala, Herman Anderson & Jen-Tse Cheng

Authors
  1. Muhammad Mujtaba
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  2. Abdallah Sassine Geara
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  3. Machaiah Madhrira
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  4. Rajesh Agarwala
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  5. Herman Anderson
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  6. Jen-Tse Cheng
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  7. Sumit Mohan
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Correspondence to Abdallah Sassine Geara.

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Mujtaba, M., Geara, A.S., Madhrira, M. et al. Toxicokinetics of metformin-associated lactic acidosis with continuous renal replacement therapy. Eur J Drug Metab Pharmacokinet 37, 249–253 (2012). https://doi.org/10.1007/s13318-012-0104-y

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  • DOI: https://doi.org/10.1007/s13318-012-0104-y

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