Does P-glycoprotein contribute to amphotericin B epithelial transport in Caco-2 cells?
Bibliographic record
Abstract
INTRODUCTION: Amphotericin B (AmB) is a highly efficacious therapeutic for invasive fungal infections and protozoal diseases. Increasing prevalence of these conditions warrants the development of an oral AmB formulation. Efflux transporters, such as the ABCB1 gene product P-glycoprotein, affect the oral bioavailability and disposition of a range of clinically relevant compounds. At present, it remains to be determined whether AmB is a substrate of P-glycoprotein mediated efflux. The objective of this study was to determine whether P-glycoprotein contributes to the epithelial transport of AmB in a Caco-2 cell model. METHODS: Stimulation of P-glycoprotein ATPase activity was assessed using membranes containing human recombinant P-glycoprotein. An ABCB1 knockdown Caco-2 cell model was employed to determine non-toxic concentrations of AmB. AmB cellular association, following a 180 min incubation, was determined using an high performance liquid chromatography-ultraviolet (HPLC-UV) assay. RESULTS: At the concentrations investigated, AmB did not stimulate P-glycoprotein ATPase activity. Non-toxic concentrations of AmB were 1 μg/mL-5 μg/mL; these were used in subsequent experiments. No significant difference in AmB cellular association was observed for ABCB1 small interfering ribonucleic acid transfected and non-transfected Caco-2 cells, following a 180 min incubation with 1 μg/mL and 2.5 μg/mL AmB. However, significantly greater AmB was associated with transfected cells as compared to non-transfected cells, when cells were incubated with 5 μg/mL AmB. CONCLUSIONS: These results suggest that AmB is not a substrate of P-glycoprotein mediated efflux in this Caco-2 cell model. P-glycoprotein is not expected to be a major barrier to the oral absorption and disposition of AmB.
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How this classification was reachedexpand
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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".