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• W2173726756 abstract "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. 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]. 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]. These results suggest that famotidine may improve the bioavailability and enhance the renal clearance of metformin." @default.
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• W2173726756 date "2015-11-23" @default.
• W2173726756 modified "2023-10-16" @default.
• W2173726756 title "The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin" @default.
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• W2173726756 doi "https://doi.org/10.1007/s40262-015-0346-3" @default.
• W2173726756 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4876051" @default.
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