Fruit juices inhibit organic anion transporting polypeptide–mediated drug uptake to decrease the oral availability of fexofenadine
Why this work is in the frame
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Bibliographic record
Abstract
OBJECTIVES: Our objective was to examine the effect of different fruits and their constituents on P-glycoprotein and organic anion transporting polypeptide (OATP) activities in vitro and on drug disposition in humans. METHODS: P-glycoprotein-mediated digoxin or vinblastine efflux was determined in polarized epithelial cell monolayers. OATP-mediated fexofenadine uptake was measured in a transfected cell line. The oral pharmacokinetics of 120 mg fexofenadine was assessed with water, 25%-strength grapefruit juice, or normal-strength grapefruit, orange, or apple juices (1.2 L over 3 hours) in a randomized 5-way crossover study in 10 healthy subjects. RESULTS: Grapefruit juice and segments and apple juice at 5% of normal strength did not alter P-glycoprotein activity. Grapefruit extract reduced transport. 6',7'-Dihydroxybergamottin had modest inhibitory activity (50% inhibitory concentration [IC(50)], 33 micromol/L). In contrast, grapefruit, orange, and apple juices at 5% of normal strength markedly reduced human OATP and rat oatp activity. 6',7'-Dihydroxybergamottin potently inhibited rat oatp3 and oatp1 (IC(50), 0.28 micromol/L). Other furanocoumarins and bioflavonoids also reduced rat oatp3 activity. Grapefruit, orange, and apple juices decreased the fexofenadine area under the plasma concentration-time curve (AUC), the peak plasma drug concentration (C(max)), and the urinary excretion values to 30% to 40% of those with water, with no change in the time to reach C(max), elimination half-life, renal clearance, or urine volume in humans. Change in fexofenadine AUC with juice was variable among individuals and inversely dependent on value with water. CONCLUSIONS: Fruit juices and constituents are more potent inhibitors of OATPs than P-glycoprotein activities, which can reduce oral drug bioavailability. Results support a new model of intestinal drug absorption and mechanism of food-drug interaction.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it