Pharmacokinetics of metformin in patients with gastrointestinal intolerance

L. McCreight, T. B. Stage, P. Connelly, M. Lonergan, F. Nielsen, C. Prehn, J. Adamski, K. Brosen, E. R. Pearson (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

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.
Original languageEnglish
Pages (from-to)1593-1601
Number of pages9
JournalDiabetes, Obesity & Metabolism
Volume20
Issue number7
Early online date19 Feb 2018
DOIs
Publication statusPublished - 1 Jul 2018

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Metformin
Pharmacokinetics
Bile Acids and Salts
Lactic Acid
Serotonin
Enterocytes
Intestines
Phenotype
Glucose

Keywords

  • antidiabetic drug
  • metformin
  • pharmacokinetics
  • type 2 diabetes
  • Body Mass Index
  • Gastrointestinal Diseases/blood
  • Severity of Illness Index
  • Abdominal Pain/etiology
  • Overweight/complications
  • Humans
  • Middle Aged
  • Half-Life
  • Male
  • Metabolic Clearance Rate
  • Serotonin/blood
  • Diabetes Mellitus, Type 2/complications
  • Lactic Acid/blood
  • Diarrhea/etiology
  • Metformin/adverse effects
  • Female
  • Aged
  • Bile Acids and Salts/blood
  • Hypoglycemic Agents/adverse effects
  • Cohort Studies

Cite this

McCreight, L. ; Stage, T. B. ; Connelly, P. ; Lonergan, M. ; Nielsen, F. ; Prehn, C. ; Adamski, J. ; Brosen, K. ; Pearson, E. R. / Pharmacokinetics of metformin in patients with gastrointestinal intolerance. In: Diabetes, Obesity & Metabolism. 2018 ; Vol. 20, No. 7. pp. 1593-1601.
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abstract = "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.",
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author = "L. McCreight and Stage, {T. B.} and P. Connelly and M. Lonergan and F. Nielsen and C. Prehn and J. Adamski and K. Brosen and Pearson, {E. R.}",
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Pharmacokinetics of metformin in patients with gastrointestinal intolerance. / McCreight, L.; Stage, T. B.; Connelly, P.; Lonergan, M.; Nielsen, F.; Prehn, C.; Adamski, J.; Brosen, K.; Pearson, E. R. (Lead / Corresponding author).

In: Diabetes, Obesity & Metabolism, Vol. 20, No. 7, 01.07.2018, p. 1593-1601.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacokinetics of metformin in patients with gastrointestinal intolerance

AU - McCreight, L.

AU - Stage, T. B.

AU - Connelly, P.

AU - Lonergan, M.

AU - Nielsen, F.

AU - Prehn, C.

AU - Adamski, J.

AU - Brosen, K.

AU - Pearson, E. R.

N1 - Funding: Wellcome Trust (GrantNumber(s): 102820/Z/13/Z; Grant recipient(s): EWAN R PEARSON); Anonymous Trust (GrantNumber(s): 218 804903)

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

KW - antidiabetic drug

KW - metformin

KW - pharmacokinetics

KW - type 2 diabetes

KW - Body Mass Index

KW - Gastrointestinal Diseases/blood

KW - Severity of Illness Index

KW - Abdominal Pain/etiology

KW - Overweight/complications

KW - Humans

KW - Middle Aged

KW - Half-Life

KW - Male

KW - Metabolic Clearance Rate

KW - Serotonin/blood

KW - Diabetes Mellitus, Type 2/complications

KW - Lactic Acid/blood

KW - Diarrhea/etiology

KW - Metformin/adverse effects

KW - Female

KW - Aged

KW - Bile Acids and Salts/blood

KW - Hypoglycemic Agents/adverse effects

KW - Cohort Studies

U2 - 10.1111/dom.13264

DO - 10.1111/dom.13264

M3 - Article

VL - 20

SP - 1593

EP - 1601

JO - Diabetes, Obesity & Metabolism

JF - Diabetes, Obesity & Metabolism

SN - 1462-8902

IS - 7

ER -