Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters

Abstract

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.

Keywords: drug interaction; genetic polymorphism; metformin; pharmacokinetics; trimethoprim.

© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

Figures

Figure 1

Schematic diagram of metformin transport within the body. Abbreviations are as follows: MATE, multidrug and toxin extrusion transporter; OCT, organic cation transporter; and PMAT, plasma membrane monoamine transporter. Missing arrowheads indicate unclear direction of transport. Question marks indicate fragmentary evidence

Figure 2

(A) Concentration–time profiles of metformin in healthy volunteers after oral administration of 500 mg three times daily (filled circles) and during cotreatment with trimethoprim (open circles). (B) Volunteers wild-type (wt) for MATE1 and OCT2. (C) Volunteers with polymorphic (poly) MATE1 (rs2289669) and wild-type OCT2. (D) Volunteers with wild-type MATE1 and polymorphic OCT2 (rs316019). (E) Volunteers with polymorphic MATE1 and OCT2. Each point represents the mean ± SEM. *P < 0.05 and **P < 0.01 (comparison at the respective time point)