Pharmacokinetics of metformin in patients with gastrointestinal intolerance

Laura J McCreight, Tore B Stage, Paul Connelly, Mike Lonergan, Flemming Nielsen, Cornelia Prehn, Jerzy Adamski, Kim Brøsen, Ewan R Pearson, Laura J McCreight, Tore B Stage, Paul Connelly, Mike Lonergan, Flemming Nielsen, Cornelia Prehn, Jerzy Adamski, Kim Brøsen, Ewan R Pearson

Abstract

Aims: To assess potential causes of metformin intolerance, including altered metformin uptake from the intestine, increased anaerobic glucose utilization and subsequent lactate production, altered serotonin uptake, and altered bile acid pool.

Methods: For this pharmacokinetic study, we recruited 10 severely intolerant and 10 tolerant individuals, matched for age, sex and body mass index. A single 500-mg dose of metformin was administered, with blood sampling at 12 time points over 24 hours. Blood samples were analysed for metformin, lactate, serotonin and bile acid concentrations, and compared across the phenotypes.

Results: The intolerant individuals were severely intolerant to 500 mg metformin. No significant difference was identified between tolerant and intolerant cohorts in metformin pharmacokinetics: median (interquartile range [IQR]) peak concentration 2.1 (1.7-2.3) mg/L and 2.0 (1.8-2.2) mg/L, respectively (P = .76); time to peak concentration 2.5 hours; median (IQR) area under the curve (AUC)0-24 16.9 (13.9-18.6) and 13.9 (12.9-16.8) mg/L*h, respectively (P = .72). Lactate concentration peaked at 3.5 hours, with mean peak concentration of 2.4 mmol/L in both cohorts (95% CI 2.0-2.8 and 1.8-3.0 mmol/L, respectively), and similar incremental AUC0-24 in each cohort: tolerant cohort 6.98 (95% CI 3.03-10.93) and intolerant cohort 4.47 (95% CI -3.12-12.06) mmol/L*h (P = .55). Neither serotonin nor bile acid concentrations were significantly different.

Conclusions: Despite evidence of severe intolerance in our cohort, there was no significant difference in metformin pharmacokinetics or systemic measures of lactate, serotonin or bile acids. This suggests that metformin intolerance may be attributable to local factors within the lumen or enterocyte.

Keywords: antidiabetic drug; metformin; pharmacokinetics; type 2 diabetes.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Symptoms of metformin intolerance by phenotype, after a single dose of metformin, 500 mg
Figure 2
Figure 2
Plasma concentration of metformin over time, after a single dose of 500 mg given at time 0 hours. Data points are mean ± SEM
Figure 3
Figure 3
Mean lactate concentration over time, after a single dose of metformin 500 mg at time 0 hours. Data points are mean ± SEM

References

    1. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002;137:25‐33.
    1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in Type 2 diabetes, 2015: a patient‐centered approach: update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140‐149.
    1. National Institute for Health and Care Excellence . Type 2 Diabetes: The Management of Type 2 Diabetes [NG28]. London: NICE; 2015.
    1. Prospective Diabetes Study (UKPDS) Group . 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.
    1. United Kingdom Prospective Diabetes Study Group. UK Prospective Diabetes Study 24: relative efficacy of sulfonylurea, insulin and metformin therapy in newly diagnosed non‐insulin dependent diabetes with primary diet failure followed for six years. Ann Intern Med. 1998;128:165‐175.
    1. Kao J, Tobis J, Mc Clelland RL. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol. 2004;93:1347‐1350. .
    1. Kooy A, de Jager J, Lehert P. Long‐term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169:616‐625. .
    1. Johnson JA, Majumdar SR, Simpson SH. Decreased mortality associated with the use of metformin compared with sulfonylurea Monotherapy in type 2 diabetes. Diabetes Care. 2002;25:2244‐2248. .
    1. McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59:426‐435. .
    1. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50:81‐98. .
    1. Han TK, Proctor WR, Costales CL, Cai H, Everett RS, Thakker DR. Four cation‐selective transporters contribute to apical uptake and accumulation of metformin in Caco‐2 cell monolayers. J Pharmacol Exp Ther. 2015;352:519‐528. .
    1. Dujic T, Zhou K, Donnelly LA, Tavendale R, Palmer CN, Pearson ER. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes. 2015;64:1786‐1793. .
    1. Zhou K, Donnelly L, Yang J, et al. Heritability of variation in glycaemic response to metformin: a genome‐wide complex trait analysis. Lancet Diabetes Endocrinol. 2014;2:481‐487. .
    1. Dujic T, Zhou K, Tavendale R, Palmer CNA, Pearson ER. Effect of serotonin transporter 5HTTLPR polymorphism on gastrointestinal intolerance to metformin: a GoDARTS study. Diabetes Care. 2016;39(11):1896‐1901. .
    1. Christensen MM, Brasch‐Andersen C, Green 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):837‐850. .
    1. Bailey CJ, Wilcock C, Scarpello JHB. Metformin and the intestine. Diabetologia. 2008;51:1552‐1553. .
    1. Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;24:49‐57. .
    1. Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol. 1992;105:1009‐1013. .
    1. Bailey CJ, Mynett KJ, Page T. Importance of the intestine as a site of metformin‐stimulated glucose utilization. Br J Pharmacol. 1994;112:671‐675. .
    1. Davis TM, Jackson D, Davis WA, Bruce DG, Chubb P. The relationship between metformin therapy and the fasting plasma lactate in type 2 diabetes: the Fremantle Diabetes Study. Br J Clin Pharmacol. 2001;52:137‐144. .
    1. Cubeddu LX, Bönisch H, Göthert M, et al. Effects of metformin on intestinal 5‐hydroxytryptamine (5‐HT) release and on 5‐HT3 receptors. Naunyn Schmiedebergs Arch Pharmacol. 2000;361:85‐91. .
    1. Yee SW, Lin L, Merski M, et al. Prediction and validation of enzyme and transporter off‐targets for metformin. J Pharmacokinet Pharmacodyn. 2015;42:463‐475. .
    1. Sikander A, Rana SV, Prasad KK. Role of serotonin in gastrointestinal motility and irritable bowel syndrome. Clin Chim Acta. 2009;403(1–2):47‐55. .
    1. Camilleri M. Serotonin in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes. 2009;16(1):53‐59.
    1. Deiteren A, De Man JG, Pelckmans PA, De Winter BY. Histamine H4 receptors in the gastrointestinal tract. Br J Pharmacol. 2015;172(5):1165‐1178. .
    1. Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diabet Med. 1998;15:651‐656. .
    1. Chiang JYL. Bile Acid Metabolism and Signaling. Compr Physiol. 2013;3(3):1191‐1212. .
    1. Takamine F, Imamura T. Isolation and characterization of bile acid 7‐dehydroxylating bacteria from human feces. Microbiol Immunol. 1995;39:11‐18. .
    1. Begley M, Gahan CGM, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev. 2005;29:625‐651. .
    1. Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99‐103. .
    1. Stage TB, Brøsen K, Christensen MMH. A comprehensive review of drug–drug interactions with metformin. Clin Pharmacokinet. 2015;54:811‐824. .
    1. Scheen A, de Magalhanes A, Salvatore T. Reduction of the acute bioavailability of metformin by the α glycosidase inhibitor acarbose in normal man. Eur J Clin Invest. 1994;24(suppl 3):50‐54.
    1. Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C, Madhusudan Rao Y. Effect of cephalexin on the pharmacokinetics of metformin in healthy human volunteers. Drug Metabol Drug Interact. 2002;19(1):41‐48.
    1. Somogyi A, Stockley C, Keal J, Rolan P, Bochner F. Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987;23(5):545‐551.
    1. Zong J, Borland J, Jerva F, Wynne B, Choukour M, Song I. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Int AIDS Soc. 2014;17(4, suppl 3):19584.
    1. Kusuhara H, Ito S, Kumagai Y, et al. Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. Clin Pharmacol Ther. 2001;89:837‐844. .
    1. Zack J, Berg J, Juan A, et al. Pharmacokinetic drug–drug interaction study of ranolazine and metformin in subjects with type 2 diabetes mellitus. Clin Pharmacol Drug Dev. 2015;4:121‐129.
    1. Müller F, Pontones CA, Renner B, et al. N(1)‐methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin–trimethoprim interaction. Eur J Clin Pharmacol. 2015;71:85‐94.
    1. Johansson S, Read J, Oliver S, et al. Pharmacokinetic evaluations of the co‐administrations of vandetanib and metformin, digoxin, midazolam, omeprazole or ranitidine. Clin Pharmacokinet. 2014;53:837‐847.
    1. DIRECT ‐ Innovative Medicines Initiative: DIabetes REsearCh on patient straTification. . Accessed October 30, 2017.
    1. Hébert H, Shepherd B, Milburn K, et al. Cohort profile: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS). Int J Epidemiol. 2017. [Epub ahead of print].
    1. Najib N, Idkaidek N, Beshtawi M, et al. Bioequivalence evaluation of two brands of metformin 500mg tablets (dialon &glucophage) in healthy human volunteers. Biopharm Drug Dispos. 2002;23:301‐306.
    1. Acharya C, Hooker AC, Türkyýlmaz GY, Jönsson S, Karlsson MO. A diagnostic tool for population models using non‐compartmental analysis: the ncappc package for R. Comput Methods Programs Biomed. 2016;127:83‐93.
    1. Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia. 2013;56(9):1898‐1906. .
    1. Shu Y, Brown C, Castro R, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008;83(2):273‐280. .
    1. Christensen MMH, Højlund K, Hother‐Nielsen O, et al. Steady‐state pharmacokinetics of metformin is independent of the OCT1 genotype in healthy volunteers. Eur J Clin Pharmacol. 2015;71:691 .
    1. Tucker GT, Casey C, Phillips PJ, Connor H, Ward JD, Woods HF. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol. 1981;12:235‐246.
    1. Robert F, Fendri S, Hary L, Lacroix C, Andréjak M, Lalau JD. Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects. Diabetes Metab. 2003;29:279‐283.
    1. Woerle HJ, Meyer C, Dostou JM, et al. Pathways for glucose disposal after meal ingestion in humans. Am J Physiol Endocrinol Metab. 2003;284:E716‐E725. .

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe