Pharmacokinetics of metformin in patients with gastrointestinal intolerance |
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| Authors: | Laura J. McCreight MBChB Tore B. Stage PhD Paul Connelly MBChB Mike Lonergan PhD Flemming Nielsen PhD Cornelia Prehn PhD Jerzy Adamski PhD Kim Brøsen PhD Ewan R. Pearson PhD |
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| Affiliation: | 1. Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, UK;2. Department of Public Health, Clinical Pharmacology and Pharmacy, University of Southern Denmark, Odense, Denmark;3. Institute of Experimental Genetics, Genome Analysis Center, Munich, Germany;4. German Research Centre for Environmental Health, Neuherberg, Germany;5. Lehrstuhl für Experimentelle Genetik, Technische Universit?t München, Freising‐Weihenstephan, Munich, Germany;6. German Centre for Diabetes Research (DZD), Munich‐Neuherberg, Munich, Germany |
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| 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. |
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| Keywords: | antidiabetic drug metformin pharmacokinetics type 2 diabetes |
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