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The effect of dipyridamole on the pharmacokinetics of metformin: a randomized crossover study in healthy volunteers.

ABSTRACT: Concomitant treatment with the glucose-lowering drug metformin and the platelet aggregation inhibitor dipyridamole often occurs in patients with type 2 diabetes mellitus who have suffered a cerebrovascular event. The gastrointestinal uptake of metformin is mediated by the human equilibrative nucleoside transporter 4 (ENT4), which is inhibited by dipyridamole in preclinical studies. We hypothesized that dipyridamole lowers the plasma exposure to metformin.Eighteen healthy volunteers (mean age 23 years; 9 male) were randomized in an open-label crossover study. Subjects were allocated to treatment with metformin 500 mg twice daily in combination with dipyridamole slow-release 200 mg twice daily or to metformin alone for 4 days. After a washout period of 10 days, the volunteers were crossed over to the alternative treatment arm. Blood samples were collected during a 10-h period after intake of the last metformin dose. The primary endpoint was the area under the plasma concentration-time curve (AUC0-12h) and the maximum plasma metformin concentration (C max).In healthy subjects, dipyridamole did not significantly affect Cmax nor AUC0-12h of metformin under steady-state conditions.Previous in vitro studies report that dipyridamole inhibits the ENT4 transporter that mediates gastrointestinal uptake of metformin. In contrast, co-administration of dipyridamole at therapeutic dosages to healthy volunteers does not have a clinically relevant effect on metformin plasma steady-state exposure. This observation is reassuring for patients who are treated with this combination of drugs.

SUBMITTER: El Messaoudi S

PROVIDER: S-EPMC4869751 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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The effect of dipyridamole on the pharmacokinetics of metformin: a randomized crossover study in healthy volunteers.

El Messaoudi S S Russel F G FG Colbers A A Bandell C C J G CC van den Broek P H H PH Burger D M DM Rongen G A GA Riksen N P NP

European journal of clinical pharmacology 20160315 6

<h4>Purpose</h4>Concomitant treatment with the glucose-lowering drug metformin and the platelet aggregation inhibitor dipyridamole often occurs in patients with type 2 diabetes mellitus who have suffered a cerebrovascular event. The gastrointestinal uptake of metformin is mediated by the human equilibrative nucleoside transporter 4 (ENT4), which is inhibited by dipyridamole in preclinical studies. We hypothesized that dipyridamole lowers the plasma exposure to metformin.<h4>Methods</h4>Eighteen ...[more]

PMID: 26979520

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Project description:In the proximal tubule, basic drugs are transported from the renal cells to the tubule lumen through the concerted action of the H(+)/organic cation antiporters, multidrug and toxin extrusion (MATE) 1 and MATE2K. Dual inhibitors of the MATE transporters have been shown to have a clinically relevant effect on the pharmacokinetics of concomitantly administered basic drugs. However, the clinical impact of selective renal organic cation transport inhibition on the pharmacokinetics and pharmacodynamics of basic drugs, such as metformin, is unknown. This study sought to identify a selective MATE2K inhibitor in vitro and to determine its clinical impact on the pharmacokinetics and pharmacodynamics of metformin in healthy subjects.Strategic cell-based screening of 71 US Food and Drug Administration (FDA)-approved medications was conducted to identify selective inhibitors of renal organic cation transporters that are capable of inhibiting at clinically relevant concentrations. From this screen, nizatidine was identified and predicted to be a clinically potent and selective inhibitor of MATE2K-mediated transport. The effect of nizatidine on the pharmacokinetics and pharmacodynamics of metformin was evaluated in 12 healthy volunteers in an open-label, randomized, two-phase crossover drug-drug interaction (DDI) study.In healthy volunteers, the MATE2K-selective inhibitor nizatidine significantly increased the apparent volume of distribution, half-life, and hypoglycemic activity of metformin. However, despite achieving unbound maximum concentrations greater than the in vitro inhibition potency (concentration of drug producing 50% inhibition [IC50]) of MATE2K-mediated transport, nizatidine did not affect the renal clearance (CLR) or net secretory clearance of metformin.This study demonstrates that a selective inhibition of MATE2K by nizatidine affected the apparent volume of distribution, tissue concentrations, and peripheral effects of metformin. However, nizatidine did not alter systemic concentrations or the CLR of metformin, suggesting that specific MATE2K inhibition may not be sufficient to cause renal DDIs with metformin.

Dataset Information

The effect of dipyridamole on the pharmacokinetics of metformin: a randomized crossover study in healthy volunteers.

Publications

The effect of dipyridamole on the pharmacokinetics of metformin: a randomized crossover study in healthy volunteers.

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