STEADY-STATE PHARMACOKINETICS OF METFORMIN IN OBESE PATIENTS WITH TYPE 2 DIABETES MELLITUS: A PRELIMINARY STUDY
DOI:
https://doi.org/10.22159/ajpcr.2017.v10i1.15252Abstract
Objective: This study aimed to determine the metformin plasma steady-state concentration (PSSC) either trough and peak level in Type 2 diabetes
mellitus patients with obesity and the impact of SLC22A1 gene organic cation transporter 1 (OCT) rs628031 A>G on PSSC of metformin.
Methods: Validated reversed-phase high-performance liquid chromatography method with ultraviolet detector was used to determine the metformin
PSSC, as well as genotype variation was performed using the restriction fragment length polymorphisms-polymerase chain reaction method.
Results: A total of 13 patients were recruited from five Primary Health Centers in Yogyakarta Province of Indonesia. The results showed that the
means of their trough and peak PSSC were 0.285±0.192 and 1.175±0.814 μg/ml, respectively. Only 10 patients (77%) had peak PSSC within the
plasma therapeutic level (PTL) of metformin, and 14-fold variability was observed for the peak PSSC. None of the patients achieved the PTL of
metformin with regard to their trough PSSC. The PSSC of metformin was independent of the OCT1 genotype in rs628031 (A>G) 408M/V SLC22A1.
Conclusion: This study found a huge variability in the trough concentration of metformin (>100-fold) and 14-fold for the peak PSSC, and no impact
of a variant of rs628013 SLC22A1 OCT1 on metformin PSSC was revealed.
Keywords: Metformin, Steady-state pharmacokinetics, Obesity, Type 2 diabetes mellitus.
Downloads
References
Hollander P. Anti-diabetes and anti-obesity medications: Effects on weight in people with diabetes. Diabetes Spectr 2007;20(3):159-65.
Golay A. Metformin and body weight. Int J Obes (Lond) 2008(1);32:61-72.
Malin SK, Kashyap SR. Effects of metformin on weight loss: Potential mechanisms. Curr Opin Endocrinol Diabetes Obes 2014;21(5):323-9.
Green B, Duffull SB. What is the best size descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol 2004;58(2):119-33.
Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: Results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997;103(6):491-7.
Ghobadi C, Johnson TN, Aarabi M, Almond LM, Allabi AC, Rowland-Yeo K, et al. Application of a systems approach to the bottom-up assessment of pharmacokinetics in obese patients: Expected variations in clearance. Clin Pharmacokinet 2011;50(12):809-22.
Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011;50(2):81-98.
Ghose R. Clinical consequences of altered drug disposition in obesity. J Clin Trials 2012;2:e107.
Ritscel W, Kearns G. Handbook of Basic Pharmacokinetics including Clinical Applications. 6th ed. Washington DC: American Pharmacist Association; 2004.
Duong JK, Kumar SS, Kirkpatrick CM, Greenup LC, Arora M, Lee TC, et al. Population pharmacokinetics of metformin in healthy subjects and patients with Type 2 diabetes mellitus: Simulation of doses according to renal function. Clin Pharmacokinet 2013;52(5):373-84.
Frid A, Sterner GN, Löndahl M, Wiklander C, Cato A, Vinge E, et al. Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: Clinical recommendations. Diabetes Care 2010;33(6):1291-3.
Christensen MM, Brasch-Andersen C, Green H, Nielsen F, Damkier P, Beck-Nielsen H, et al. The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenet Genomics 2011;21(12):837-50.
Stage TB, Damkier P, Pedersen RS, Christensen MM, Christiansen L, Christensen K, et al. A twin study of the trough plasma steady-state concentration of metformin. Pharmacogenet Genomics 2015;25(5):259-62.
Müller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol 2005;70(12):1851-60.
Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE. Metformin pathways: Pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 2012;22(11):820-7.
Umamaheswaran G, Praveen RG, Arunkumar AS, Das AK, Shewade DG, Adithan C. Genetic analysis of OCT1 gene polymorphisms in an Indian population. Indian J Hum Genet 2011;17(3):164-8.
Rojas LB, Gomes MB. Metformin: An old but still the best treatment for Type 2 diabetes. Diabetol Metab Syndr 2013;5(1):6.
American Pharmacist Association. Drug Information Handbook. 20th ed. Ohio, USA: Lexi-Comp; 2012.
Bardin C, Nobecourt E, Larger E, Chast F, Treluyer JM, Urien S. Population pharmacokinetics of metformin in obese and non-obese patients with Type 2 diabetes mellitus. Eur J Clin Pharmacol 2012;68(6):961-8.
Shargel L, Wu-Pong S, Yu AB. Applied Biopharmaceutics and Pharmacokinetics. New York: Appleton & Lange Reviews, McGraw Hill; 2005.
Roohk HV, Zaidi AR. A review of glycated albumin as an intermediate glycation index for controlling diabetes. J Diabetes Sci Technol 2008;2(6):1114-21.
Chen M, Nafziger AN, Drusano GL, Ma L, Bertino JS Jr. Comparative pharmacokinetics and pharmacodynamic target attainment of ertapenem in normal-weight, obese, and extremely obese adults. Antimicrob Agents Chemother 2006;50(4):1222-7.
Gross AS. Best practice in therapeutic drug monitoring. Br J Clin Pharmacol 2001;52 Suppl 1:5S-10S.
Bruijstens LA, van Luin M, Buscher-Jungerhans PM, Bosch FH. Reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment. Neth J Med 2008;66(5):185-90.
Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011;50(2):81-98.
Hong Y, Rohatagi S, Habtemariam B, Walker JR, Schwartz SL, Mager DE. Population exposure-response modeling of metformin in patients with Type 2 diabetes mellitus. J Clin Pharmacol 2008;48(6):696-707.
Tahrani AA, Varughese GI, Scarpello JH, Hanna FW. Metformin, heart failure, and lactic acidosis: Is metformin absolutely contraindicated? BMJ 2007;335(7618):508-12.
Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin. BMJ 2003;326(7379):4-5.
Saveetha V, Sundaram IS, Shanmugasundaram P. A prospective study on the efficacy of metformin in obese and non-obese patients with polycyctic ovary syndrome. Asian J Pharm Clin Res 2016;9 Suppl 1:145-7.
Yaseer MK, Abbas MR, Saba H. The effect of metformin on cytokines in Iraqi patients with type 2 diabetes. Innovare J Med Sci 2013;1(3):4-10.
Yang C, Li H, Wang Z, Zhang W, Zhou K, Meng J, et al. Glycated albumin is a potential diagnostic tool for diabetes mellitus. Clin Med (Lond) 2012;12(6):568-71.
Sumitani S, Morita S, Deguchi R, Hirai K, Mukai K, Utsu Y, et al. Metformin decreases glycated albumin to glycated haemoglobin ratio in patients with newly diagnosed Type 2 diabetes. Ann Clin Biochem 2015;52(1):76-81.
Tzvetkov MV, Vormfelde SV, Balen D, Meineke I, Schmidt T, Sehrt D, et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther 2009;86(3):299-306.
Shikata E, Yamamoto R, Takane H, Shigemasa C, Ikeda T, Otsubo K, et al. Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin. J Hum Genet 2007;52(2):117-22.
Tarasova L, Kalnina I, Geldnere K, Bumbure A, Ritenberga R, Nikitina-Zake L, et al. Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin Extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated Type 2 diabetes patients. Pharmacogenet Genomics 2012;22(9):659-66.
Klen J, Goricar K, Janež A, Dolžan V. The role of genetic factors and kidney and liver function in glycemic control in Type 2 diabetes patients on long-term metformin and sulphonylurea cotreatment. Biomed Res Int 2014;2014:934729.
Published
How to Cite
Issue
Section
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.
