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Here, the SNARF-1 AM methodology was optimized. The identified bicarbonate extrusion mechanisms were partially inhibited, and measurements were carried out in a medium with lower intrinsic fluorescence, with no need for controlling external CO2 levels. We applied the assay for the screening of flavonoids as potential bitter-masking compounds for guaifenesin, a bitter-tasting antitussive drug. Our findings revealed that eriodictyol, hesperitin and phyllodulcin were the most potent suitable candidates for bitter-masking activity, verified