Pharmacokinetics of metformin in patients with gastrointestinal intolerance

Aims: Metformin intolerance symptoms are gastrointestinal in nature, but the underlying mechanism is poorly understood. The aim of this study was to assess potential causes of metformin intolerance including: altered metformin uptake from the intestine; increased anaerobic glucose utilisation and subsequent lactate production; altered serotonin uptake; and altered bile acid pool.

Methods: This pharmacokinetic study recruited ten severely intolerant and ten tolerant individuals matched for age, sex and BMI. A single 500mg dose of metformin was administered, with blood sampling at eleven 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 500mg metformin. No significant difference was identified between tolerant and intolerant cohorts in metformin pharmacokinetics: median Cmax 2.1 (IQR 1.7 – 2.3) and 2.0 (IQR 1.8 – 2.2) mg/L respectively (p = 0.76); tmax 2.5 hours; median AUC0-24 16.9 (IQR 13.9 – 18.6) and 13.9 (IQR 12.9 – 16.8) (mg/L)*h respectively (p = 0.72). Lactate concentration peaked at 3.5 hours, with mean peak concentration of 2.4 mmol/L in both cohorts (95% CIs 2.0 – 2.8, and 1.8 – 3.0 mmol/L respectively), and comparable iAUC0-24: tolerant 6.98 (3.03 –10.93) and intolerant 4.47 (-3.12 – 12.06) mmol/L*h, (p=0.55). 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 due to local factors within the lumen or enterocyte.