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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 6/2016

01-06-2016 | Original Research Article

The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin

Authors: Jennifer E. Hibma, Arik A. Zur, Richard A. Castro, Matthias B. Wittwer, Ron J. Keizer, Sook Wah Yee, Srijib Goswami, Sophie L. Stocker, Xuexiang Zhang, Yong Huang, Claire M. Brett, Radojka M. Savic, Kathleen M. Giacomini

Published in: Clinical Pharmacokinetics | Issue 6/2016

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Abstract

Introduction

Pharmacokinetic outcomes of transporter-mediated drug–drug interactions (TMDDIs) are increasingly being evaluated clinically. The goal of our study was to determine the effects of selective inhibition of multidrug and toxin extrusion protein 1 (MATE1), using famotidine, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers.

Methods

Volunteers received metformin alone or with famotidine in a crossover design. As a positive control, the longitudinal effects of famotidine on the plasma levels of creatinine (an endogenous substrate of MATE1) were quantified in parallel. Famotidine unbound concentrations in plasma reached 1 µM, thus exceeding the in vitro concentrations that inhibit MATE1 [concentration of drug producing 50 % inhibition (IC50) 0.25 µM]. Based on current regulatory guidance, these concentrations are expected to inhibit MATE1 clinically [i.e. maximum unbound plasma drug concentration (C max,u)/IC50 >0.1].

Results

Consistent with MATE1 inhibition, famotidine administration significantly altered creatinine plasma and urine levels in opposing directions (p < 0.005). Interestingly, famotidine increased the estimated bioavailability of metformin [cumulative amount of unchanged drug excreted in urine from time zero to infinity (A e∞)/dose; p < 0.005] without affecting its systemic exposure [area under the plasma concentration–time curve (AUC) or maximum concentration in plasma (C max)] as a result of a counteracting increase in metformin renal clearance. Moreover, metformin–famotidine co-therapy caused a transient effect on oral glucose tolerance tests [area under the glucose plasma concentration–time curve between time zero and 0.5 h (AUCglu,0.5); p < 0.005].

Conclusions

These results suggest that famotidine may improve the bioavailability and enhance the renal clearance of metformin.
Appendix
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Metadata
Title
The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin
Authors
Jennifer E. Hibma
Arik A. Zur
Richard A. Castro
Matthias B. Wittwer
Ron J. Keizer
Sook Wah Yee
Srijib Goswami
Sophie L. Stocker
Xuexiang Zhang
Yong Huang
Claire M. Brett
Radojka M. Savic
Kathleen M. Giacomini
Publication date
01-06-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 6/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0346-3

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