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*

*Kontaktforfatter for dette arbejde

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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 AUC 0–24 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.

OriginalsprogEngelsk
TidsskriftDiabetes, Obesity and Metabolism
Vol/bind20
Udgave nummer7
Sider (fra-til)1593-1601
ISSN1462-8902
DOI
StatusUdgivet - jul. 2018

Fingeraftryk

Pharmacokinetics
Lactic Acid
Area Under Curve
Enterocytes
Intestines
Body Mass Index

Citer dette

Mccreight, Laura J. ; Stage, Tore B. ; Connelly, Paul ; Lonergan, Mike ; Nielsen, Flemming ; Prehn, Cornelia ; Adamski, Jerzy ; Brøsen, Kim ; Pearson, Ewan R. / Pharmacokinetics of metformin in patients with gastrointestinal intolerance. I: Diabetes, Obesity and Metabolism. 2018 ; Bind 20, Nr. 7. s. 1593-1601.
@article{ddb2db09084640119c9d2b5d36e817f1,
title = "Pharmacokinetics of metformin in patients with gastrointestinal intolerance",
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 AUC 0–24 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, type 2 diabetes, antidiabetic drug, pharmacokinetics, metformin, Gastrointestinal Diseases/blood, Overweight/complications, Humans, Middle Aged, Half-Life, Male, Metabolic Clearance Rate, Lactic Acid/blood, Female, Body Mass Index, Severity of Illness Index, Abdominal Pain/etiology, Serotonin/blood, Diabetes Mellitus, Type 2/complications, Diarrhea/etiology, Metformin/adverse effects, Aged, Bile Acids and Salts/blood, Hypoglycemic Agents/adverse effects, Cohort Studies",
author = "Mccreight, {Laura J.} and Stage, {Tore B.} and Paul Connelly and Mike Lonergan and Flemming Nielsen and Cornelia Prehn and Jerzy Adamski and Kim Br{\o}sen and Pearson, {Ewan R.}",
note = "This article is protected by copyright. All rights reserved.",
year = "2018",
month = "7",
doi = "10.1111/dom.13264",
language = "English",
volume = "20",
pages = "1593--1601",
journal = "Diabetes, Obesity and Metabolism",
issn = "1462-8902",
publisher = "Wiley-Blackwell",
number = "7",

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Mccreight, LJ, Stage, TB, Connelly, P, Lonergan, M, Nielsen, F, Prehn, C, Adamski, J, Brøsen, K & Pearson, ER 2018, 'Pharmacokinetics of metformin in patients with gastrointestinal intolerance', Diabetes, Obesity and Metabolism, bind 20, nr. 7, s. 1593-1601. https://doi.org/10.1111/dom.13264

Pharmacokinetics of metformin in patients with gastrointestinal intolerance. / Mccreight, Laura J.; Stage, Tore B.; Connelly, Paul; Lonergan, Mike; Nielsen, Flemming; Prehn, Cornelia; Adamski, Jerzy; Brøsen, Kim; Pearson, Ewan R.

I: Diabetes, Obesity and Metabolism, Bind 20, Nr. 7, 07.2018, s. 1593-1601.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Pharmacokinetics of metformin in patients with gastrointestinal intolerance

AU - Mccreight, Laura J.

AU - Stage, Tore B.

AU - Connelly, Paul

AU - Lonergan, Mike

AU - Nielsen, Flemming

AU - Prehn, Cornelia

AU - Adamski, Jerzy

AU - Brøsen, Kim

AU - Pearson, Ewan R.

N1 - This article is protected by copyright. All rights reserved.

PY - 2018/7

Y1 - 2018/7

N2 - 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 AUC 0–24 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.

AB - 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 AUC 0–24 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.

KW - Antidiabetic drug

KW - Metformin

KW - Pharmacokinetics

KW - Type 2 diabetes

KW - type 2 diabetes

KW - antidiabetic drug

KW - pharmacokinetics

KW - metformin

KW - Gastrointestinal Diseases/blood

KW - Overweight/complications

KW - Humans

KW - Middle Aged

KW - Half-Life

KW - Male

KW - Metabolic Clearance Rate

KW - Lactic Acid/blood

KW - Female

KW - Body Mass Index

KW - Severity of Illness Index

KW - Abdominal Pain/etiology

KW - Serotonin/blood

KW - Diabetes Mellitus, Type 2/complications

KW - Diarrhea/etiology

KW - Metformin/adverse effects

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 - Journal article

C2 - 29457876

VL - 20

SP - 1593

EP - 1601

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 7

ER -