Oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross‐over study

Abstract The aim of the study was to investigate if there is a clinically relevant drug interaction between metformin and codeine. Volunteers were randomized to receive on four separate occasions: (A) orally administered metformin (1 g), (B) intravenously administered metformin (0.5 g), (C) five dos...

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Autores principales:	Ida Kuhlmann, Amanda Nøddebo Nyrup, Tore Bjerregaard Stage, Mette Marie Hougaard Christensen, Troels Korshøj Bergmann, Per Damkier, Flemming Nielsen, Kurt Højlund, Kim Brøsen
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/b40ce672adc646a18fbe9434186c5a6f
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spelling	oai:doaj.org-article:b40ce672adc646a18fbe9434186c5a6f2021-11-19T17:51:35ZOral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross‐over study1752-80621752-805410.1111/cts.13107https://doaj.org/article/b40ce672adc646a18fbe9434186c5a6f2021-11-01T00:00:00Zhttps://doi.org/10.1111/cts.13107https://doaj.org/toc/1752-8054https://doaj.org/toc/1752-8062Abstract The aim of the study was to investigate if there is a clinically relevant drug interaction between metformin and codeine. Volunteers were randomized to receive on four separate occasions: (A) orally administered metformin (1 g), (B) intravenously administered metformin (0.5 g), (C) five doses of tablet codeine 25 mg; the last dose was administered together with oral metformin (1 g), and (D) five doses of tablet codeine 25 mg; the last dose was administered together with metformin (0.5 g) intravenously. Blood samples were drawn for 24 h after administration of metformin, and for 6 h after administration of codeine and analyzed using liquid chromatography and tandem mass spectrometry. Healthy volunteers genotyped as CYP2D6 normal metabolizers (1/1) without known reduced function variants in the OCT1 gene (rs12208357, rs34130495, rs34059508, and rs72552763) were invited. The median absorption fraction of metformin was 0.31 and was not influenced by codeine intake. The median time to maximum concentration (Tmax) after oral intake of metformin was 2 h without, and 3 h with codeine (p = 0.06). The geometric mean ratios of the areas under the plasma concentration time‐curve (AUCs) for morphine and its metabolites M3G and M6G for oral intake of metformin‐to‐no metformin were 1.21, 1.31, and 1.27, respectively, and for i.v. metformin‐to‐no metformin 1.28, 1.34, and 1.30, respectively. Concomitant oral and i.v. metformin increased the plasma levels of morphine, M3G and M6G. These small pharmacokinetic changes may well contribute to an increased risk of early discontinuation of metformin. Hence, a clinically relevant drug‐drug interaction between metformin and codeine seems plausible.Ida KuhlmannAmanda Nøddebo NyrupTore Bjerregaard StageMette Marie Hougaard ChristensenTroels Korshøj BergmannPer DamkierFlemming NielsenKurt HøjlundKim BrøsenWileyarticleTherapeutics. PharmacologyRM1-950Public aspects of medicineRA1-1270ENClinical and Translational Science, Vol 14, Iss 6, Pp 2408-2419 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
spellingShingle	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 Ida Kuhlmann Amanda Nøddebo Nyrup Tore Bjerregaard Stage Mette Marie Hougaard Christensen Troels Korshøj Bergmann Per Damkier Flemming Nielsen Kurt Højlund Kim Brøsen Oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross‐over study
description	Abstract The aim of the study was to investigate if there is a clinically relevant drug interaction between metformin and codeine. Volunteers were randomized to receive on four separate occasions: (A) orally administered metformin (1 g), (B) intravenously administered metformin (0.5 g), (C) five doses of tablet codeine 25 mg; the last dose was administered together with oral metformin (1 g), and (D) five doses of tablet codeine 25 mg; the last dose was administered together with metformin (0.5 g) intravenously. Blood samples were drawn for 24 h after administration of metformin, and for 6 h after administration of codeine and analyzed using liquid chromatography and tandem mass spectrometry. Healthy volunteers genotyped as CYP2D6 normal metabolizers (1/1) without known reduced function variants in the OCT1 gene (rs12208357, rs34130495, rs34059508, and rs72552763) were invited. The median absorption fraction of metformin was 0.31 and was not influenced by codeine intake. The median time to maximum concentration (Tmax) after oral intake of metformin was 2 h without, and 3 h with codeine (p = 0.06). The geometric mean ratios of the areas under the plasma concentration time‐curve (AUCs) for morphine and its metabolites M3G and M6G for oral intake of metformin‐to‐no metformin were 1.21, 1.31, and 1.27, respectively, and for i.v. metformin‐to‐no metformin 1.28, 1.34, and 1.30, respectively. Concomitant oral and i.v. metformin increased the plasma levels of morphine, M3G and M6G. These small pharmacokinetic changes may well contribute to an increased risk of early discontinuation of metformin. Hence, a clinically relevant drug‐drug interaction between metformin and codeine seems plausible.
format	article
author	Ida Kuhlmann Amanda Nøddebo Nyrup Tore Bjerregaard Stage Mette Marie Hougaard Christensen Troels Korshøj Bergmann Per Damkier Flemming Nielsen Kurt Højlund Kim Brøsen
author_facet	Ida Kuhlmann Amanda Nøddebo Nyrup Tore Bjerregaard Stage Mette Marie Hougaard Christensen Troels Korshøj Bergmann Per Damkier Flemming Nielsen Kurt Højlund Kim Brøsen
author_sort	Ida Kuhlmann
title	Oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross‐over study
title_short	Oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross‐over study
title_full	Oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross‐over study
title_fullStr	Oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross‐over study
title_full_unstemmed	Oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross‐over study
title_sort	oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: a cross‐over study
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/b40ce672adc646a18fbe9434186c5a6f
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Oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross‐over study

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