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

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 pharmacok...

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Published in:Clinical pharmacokinetics 2016-06, Vol.55 (6), p.711-721
Main Authors: Hibma, Jennifer E., Zur, Arik A., Castro, Richard A., Wittwer, Matthias B., Keizer, Ron J., Yee, Sook Wah, Goswami, Srijib, Stocker, Sophie L., Zhang, Xuexiang, Huang, Yong, Brett, Claire M., Savic, Radojka M., Giacomini, Kathleen M.
Format: Article
Language:English
Subjects:
Adult
Anti-Ulcer Agents - pharmacology
Area Under Curve
Blood Glucose
Creatinine - blood
Creatinine - urine
Cross-Over Studies
Dose-Response Relationship, Drug
Famotidine - pharmacology
Female
Humans
Hypoglycemic Agents - pharmacokinetics
Internal Medicine
Male
Medicine
Medicine & Public Health
Metformin - pharmacokinetics
Organic Cation Transport Proteins - antagonists & inhibitors
Original Research Article
Pharmacology/Toxicology
Pharmacotherapy
Young Adult
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Summary: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 (IC 50 ) 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 )/IC 50 >0.1]. Results Consistent with MATE1 inhibition, famotidine administration significantly altered creatinine plasma and urine levels in opposing directions ( p  
ISSN:0312-5963
1179-1926
DOI:10.1007/s40262-015-0346-3