Multifaceted Food Effects on Intestinal Drug Uptake Transporters: Mechanistic Insights from Small Molecules to Macromolecules
Abstract
Drug-food interactions are highly diverse, sometimes leading to clinically significant outcomes. A classic example is the contraindicated coadministration of grapefruit juice with specific medications due to the inhibition of intestinal drug-metabolizing enzymes. This review delineates the diverse mechanisms by which fruit-derived small- and macromolecules modulate intestinal transporters. First, the key determinants of intestinal drug absorption and how dietary factors influence these processes are briefly described. Polyphenols in apple, grapefruit, and orange juices competitively inhibit intestinal uptake transporter organic anion transporting polypeptide 2B1 (OATP2B1), thereby reducing the systemic exposure of its substrate drugs. Notably, apple polyphenols trigger the internalization of OATP2B1 from the plasma membrane via protein kinase C activation, a phenomenon experimentally characterized as a "pre-incubation effect." A pre-incubation effect is also induced by apple-derived extracellular vesicles (APEVs); microRNAs contained within APEVs bind to the SLCO2B1-3'UTR, leading to the down-regulation of OATP2B1 expression. Furthermore, both apple polyphenols and APEV-contained microRNAs suppress the expression of the apical sodium-dependent bile acid transporter (ASBT). Mechanistically, these apple-derived microRNAs down-regulate retinoic acid receptor alpha, a transcription factor for ASBT expression. The physiological and pharmacological relevance of these APEV effects has been demonstrated. Regarding OATP2B1, suppressing the intestinal accumulation of SN-38 significantly mitigates SN-38-induced gastrointestinal toxicity. Meanwhile, the reduction in ASBT activity aligns with the well-documented health benefits of apple consumption on functional constipation. In conclusion, fruit-derived small and macromolecules regulate intestinal uptake transporters through multifaceted mechanisms. Elucidating these pathways is essential not only for preventing adverse interactions but also for understanding and leveraging the health-promoting benefits of functional foods.
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BibTeX
@article{tamai2026multifaceted,
title = {{Multifaceted Food Effects on Intestinal Drug Uptake Transporters: Mechanistic Insights from Small Molecules to Macromolecules}},
author = {Ikumi Tamai},
journal = {Biological and Pharmaceutical Bulletin},
year = {2026},
month = sep,
doi = {10.1248/bpb.b26-00318},
url = {https://www.jstage.jst.go.jp/article/bpb/49/9/49_b26-00318/_article},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Multifaceted Food Effects on Intestinal Drug Uptake Transporters: Mechanistic Insights from Small Molecules to Macromolecules
AU - Ikumi Tamai
PY - 2026
DA - 2026/09/01
JO - Biological and Pharmaceutical Bulletin
DO - 10.1248/bpb.b26-00318
UR - https://www.jstage.jst.go.jp/article/bpb/49/9/49_b26-00318/_article
AB - Drug-food interactions are highly diverse, sometimes leading to clinically significant outcomes. A classic example is the contraindicated coadministration of grapefruit juice with specific medications due to the inhibition of intestinal drug-metabolizing enzymes. This review delineates the diverse mechanisms by which fruit-derived small- and macromolecules modulate intestinal transporters. First, the key determinants of intestinal drug absorption and how dietary factors influence these processes are briefly described. Polyphenols in apple, grapefruit, and orange juices competitively inhibit intestinal uptake transporter organic anion transporting polypeptide 2B1 (OATP2B1), thereby reducing the systemic exposure of its substrate drugs. Notably, apple polyphenols trigger the internalization of OATP2B1 from the plasma membrane via protein kinase C activation, a phenomenon experimentally characterized as a "pre-incubation effect." A pre-incubation effect is also induced by apple-derived extracellular vesicles (APEVs); microRNAs contained within APEVs bind to the SLCO2B1-3'UTR, leading to the down-regulation of OATP2B1 expression. Furthermore, both apple polyphenols and APEV-contained microRNAs suppress the expression of the apical sodium-dependent bile acid transporter (ASBT). Mechanistically, these apple-derived microRNAs down-regulate retinoic acid receptor alpha, a transcription factor for ASBT expression. The physiological and pharmacological relevance of these APEV effects has been demonstrated. Regarding OATP2B1, suppressing the intestinal accumulation of SN-38 significantly mitigates SN-38-induced gastrointestinal toxicity. Meanwhile, the reduction in ASBT activity aligns with the well-documented health benefits of apple consumption on functional constipation. In conclusion, fruit-derived small and macromolecules regulate intestinal uptake transporters through multifaceted mechanisms. Elucidating these pathways is essential not only for preventing adverse interactions but also for understanding and leveraging the health-promoting benefits of functional foods.
SN - 1347-5215
SN - 0918-6158
ER -