Pharmacokinetics of metformin in patients with gastrointestinal intolerance

McCreight, L. J., Stage, T. B., Connelly, P. , Lonergan, M., Nielsen, F., Prehn, C., Adamski, J., Brøsen, K. and Pearson, E. R. (2018) Pharmacokinetics of metformin in patients with gastrointestinal intolerance. Diabetes, Obesity and Metabolism, 20(7), pp. 1593-1601. (doi: 10.1111/dom.13264) (PMID:29457876) (PMCID:PMC6033038)

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.

• Item Type: Articles
• Additional Information: Funding information: Anonymous Trust, University of Dundee; “A. J. Andersen og hustrus Fond” (A.J. Andersen and wife's foundation); “Fonden til Lægevidenskabens Fremme” (Foundation for the promotion of Medical Sciences); German Federal Ministry of Education and Research to the German Center for Diabetes Research; Wellcome Trust New Investigator Award (102 820/Z/13/Z).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Connelly, Dr Paul
• Authors: McCreight, L. J., Stage, T. B., Connelly, P., Lonergan, M., Nielsen, F., Prehn, C., Adamski, J., Brøsen, K., and Pearson, E. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Diabetes, Obesity and Metabolism
• Publisher: Wiley
• ISSN: 1462-8902
• ISSN (Online): 1463-1326
• Published Online: 19 February 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Diabetes, Obesity and Metabolism 20(7): 1593-1601
• Publisher Policy: Reproduced under a Creative Commons License