The Forgotten First Contact: The Oral Cavity as a Site of Local Biotransformation Shaping the Chemical Form of Polyphenolic Drugs and Dietary Compounds

Background/Objectives: Polyphenols are dietary constituents and active substances in dosage forms applied locally in the mouth, yet their bioavailability is interpreted almost exclusively in terms of intestinal absorption and colonic microbial metabolism. This review examines the oral cavity as a site of local biotransformation, a compartment that can chemically modify polyphenols before absorption, and asks whether this conversion could be measured as a phenotype. Methods: Narrative synthesis is reported according to SANRA. Four databases were searched from inception to 31 August 2026. Results: Flavonoid glucosides are hydrolysed to aglycones within minutes of contact with saliva; anthocyanins are deglycosylated to cyanidin and converted to protocatechuic acid; epigallocatechin gallate is de-esterified. Local concentrations reach 2–145 μM, two orders of magnitude above plasma. Conversion capacity varied more than twenty-fold among 17 subjects in the only quantitative study. Conclusions: The oral cavity can alter the chemical form of the polyphenols presented to absorption. The orally transformed fraction of an ingested dose is small; a first-pass effect is not demonstrated, and the established consequences are local and qualitative. Oral metabotypes have not been demonstrated; the concept and its operational classification are proposed as hypotheses to be tested in adequately sized cohorts.