Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters
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Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters. / Grün, Barbara; Kiessling, Michael K; Burhenne, Jürgen; Riedel, Klaus-Dieter; Weiss, Johanna; Rauch, Geraldine; Haefeli, Walter E; Czock, David.
in: BRIT J CLIN PHARMACO, Jahrgang 76, Nr. 5, 11.2013, S. 787-796.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters
AU - Grün, Barbara
AU - Kiessling, Michael K
AU - Burhenne, Jürgen
AU - Riedel, Klaus-Dieter
AU - Weiss, Johanna
AU - Rauch, Geraldine
AU - Haefeli, Walter E
AU - Czock, David
N1 - © 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.
PY - 2013/11
Y1 - 2013/11
N2 - AIMS: Metformin pharmacokinetics depends on the presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms.METHODS: Twenty-four healthy volunteers received metformin 500 mg three times daily for 10 days and trimethoprim 200 mg twice daily from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analysed.RESULTS: In the population as a whole, trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l h(-1) and renal metformin clearance from 31 to 21 l h(-1) , and prolonged half-life from 2.7 to 3.6 h (all P < 0.01). This resulted in an increase in the maximal plasma concentration by 38% and in the area under the plasma concentration-time curve by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106 ml min(-1) (P < 0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol l(-1) (P = 0.016).CONCLUSIONS: The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin.
AB - AIMS: Metformin pharmacokinetics depends on the presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms.METHODS: Twenty-four healthy volunteers received metformin 500 mg three times daily for 10 days and trimethoprim 200 mg twice daily from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analysed.RESULTS: In the population as a whole, trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l h(-1) and renal metformin clearance from 31 to 21 l h(-1) , and prolonged half-life from 2.7 to 3.6 h (all P < 0.01). This resulted in an increase in the maximal plasma concentration by 38% and in the area under the plasma concentration-time curve by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106 ml min(-1) (P < 0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol l(-1) (P = 0.016).CONCLUSIONS: The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin.
KW - Adult
KW - Anti-Infective Agents, Urinary
KW - Area Under Curve
KW - Creatinine
KW - Drug Interactions
KW - Half-Life
KW - Humans
KW - Hypoglycemic Agents
KW - Lactic Acid
KW - Male
KW - Metformin
KW - Middle Aged
KW - Molecular Sequence Data
KW - Organic Cation Transport Proteins
KW - Polymorphism, Single Nucleotide
KW - Trimethoprim
KW - Young Adult
KW - Comparative Study
KW - Controlled Clinical Trial
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1111/bcp.12079
DO - 10.1111/bcp.12079
M3 - SCORING: Journal article
C2 - 23305245
VL - 76
SP - 787
EP - 796
JO - BRIT J CLIN PHARMACO
JF - BRIT J CLIN PHARMACO
SN - 0306-5251
IS - 5
ER -