P-Glycoprotein Efflux Inhibition by Amphiphilic Diblock Copolymers: Relationship between Copolymer Concentration and Substrate Hydrophobicity
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Bibliographic record
Abstract
The utilization of surfactants to increase intestinal absorption of drugs is a viable strategy that benefits from increases in drug solubilization and the potential for inhibition of P-glycoprotein (P-gp) mediated efflux. However, the effective concentration range for P-gp inhibition of most surfactants is defined over a narrow concentration range, below the critical micelle concentration (CMC), as a result of significant micelle sequestration of drug. Therefore, the objectives of these studies were to assess if association of P-gp substrates differing in hydrophobicity will impact the effective concentration range for P-gp inhibition by amphiphilic diblock copolymers based on methoxypolyethylene glycol-block-polycaprolatone (MePEG-b-PCL). Comparisons between the micelle association and Caco-2 cellular accumulation were evaluated using two structurally homologous P-gp substrates, the relatively hydrophobic R-6G and the hydrophilic R-123, over concentrations above and below the CMC for MePEG-b-PCL diblock copolymers. An approximately 3.75-fold enhancement of R-123 accumulation occurred with 2 mM MePEG17-b-PCL5, compared to approximately 1.25-fold for R-6G. This decrease in the accumulation enhancement corresponds with the higher R-6G fraction (0.75) associated at 2 mM MePEG17-b-PCL5 compared with R-123 (0.25). Interestingly, R-6G accumulation was enhanced over a very broad range of MePEG17-b-PCL5 concentrations below the CMC. This was in contrast to R-123, which demonstrated no enhancement below the CMC. A similar concentration dependent accumulation profile was seen with other surfactants such as vitamin E TPGS and Cremophor EL and with two other P-gp substrates differing in hydrophobicity, the relatively hydrophobic paclitaxel and hydrophilic doxorubicin. In conclusion, the effective concentration range for surfactant mediated inhibition of P-gp appears to depend on the P-gp substrate hydrophobicity.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 it