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

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Hibma JE, Zur AA, Castro RA, Wittwer MB, Keizer RJ, Yee SW, Goswami S, Stocker SL, Zhang X, Huang Y, Brett CM, Savic RM, Giacomini KM

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

Clin Pharmacokinet. 2016 Jun;55(6):711-21. doi: 10.1007/s40262-015-0346-3.

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26597253 [ View in PubMed

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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 microM, thus exceeding the in vitro concentrations that inhibit MATE1 [concentration of drug producing 50 % inhibition (IC50) 0.25 microM]. 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 einfinity)/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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Famotidine	Multidrug and toxin extrusion protein 1	Protein	Humans	No	Inhibitor	Details