Effects of Proton Pump Inhibitors on Metformin Pharmacokinetics and Pharmacodynamics

Abstract

As inhibitors of organic cation transporters (OCTs), proton pump inhibitors (PPIs) may affect the plasma levels of metformin, an OCT substrate. We investigated the effects of two PPIs, pantoprazole and rabeprazole, on metformin pharmacokinetics and glucose levels in healthy subjects. In this open, randomized, six-sequence, three-period crossover study, 24 participants were administered metformin, either alone or in combination with pantoprazole or rabeprazole. The plasma concentrations of metformin and serum concentrations of glucose after a 75-g oral glucose tolerance test (OGTT) were determined. The area under the concentration-time curve (AUC) for metformin was 15% and 16% greater following coadministration with pantoprazole and rabeprazole, respectively.The maximum plasma metformin concentrations (C max ) also increased by 15% and 22%, respectively, compared with when it was administered without the PPIs. The percentage change in the AUC for glucose concentration versus time for metformin plus rabeprazole was significantly lower than that for metformin plus pantoprazole [geometric mean ratio: 0.96 (90% confidence interval: 0.92-0.99) and 0.77 (0.63-0.93), respectively]. There was no significant difference in the maximum glucose concentration. In conclusion, concomitant administration of PPIs with metformin significantly increased plasma metformin exposure, but the effects on glucose disposition were minor and varied depending on the PPI administered.

N1-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin–trimethoprim interaction

“…Intake of metformin in the morning of day 5 was defined as study time 0 h. On days 4 (−22 h) and 5 (+2 h) of each phase, an oral glucose tolerance test (OGTT, 75 g glucose, AccuChek® Dextrose O.G-T., Roche Pharma AG, Germany) was performed in order to determine the pharmacodynamic consequences of the interaction based on previous work using OGTTs as a biomarker of metformin action [e.g., [23][24][25][26]]. The abovementioned evening dose of metformin was administered in order to have a similar study design as previous studies, which investigated metformin pharmacodynamics in healthy volunteers [23][24][25][26]. In phase B, a dose of 200 mg trimethoprim (tablets, Infectotrimet®, Infectopharm Arzneimittel und Consilium GmbH, Germany) was administered additionally p.o.…”

“…Metformin was administered additionally 12 h prior to the study day due to pharmacodynamic reasons [see "Materials and Methods", [23][24][25][26]. Plasma concentrations at t=0 h were not significantly different (without trimethoprim, 268 ± 129 ng/ml; with trimethoprim, 248±73 ng/ml) indicating a similar carryover of metformin in the two study phases.…”

Reporting Guidelines for Clinical Pharmacokinetic Studies: The ClinPK Statement

“…In the example provided in electronic supplementary Table S2, one can see that the mean half-life for metformin when taken with pantoprazole is 3.38 h [24]. However, the accompanying standard deviation of 0.69 further informs the reader that the half-life may be variable between patients.…”

Proton pump inhibitors do not impair the effectiveness of metformin in patients with diabetes

“…While this difference is very small and unlikely to have much clinical significance, we speculate that it may be due in part to amelioration by PPIs of metformin's gastrointestinal side effects, improving adherence. Alternatively, it may be due to the increase in plasma metformin concentrations with PPI co-administration described previously in healthy volunteers [8,9]. This study has limitations.…”

“…Two recent short term randomized crossover studies in healthy subjects found that co-administration of metformin with PPIs did not appear to alter metformin's effect on glucose homeostasis, but did increase the area under the curve (AUC) of metformin's plasma concentration by approximately 15% [8,9]. The authors hypothesized that the modest increase in metformin plasma concentration might actually be due to inhibition of OCT transporters, which could reduce uptake into the liver and leave more drug in the plasma.…”