Abstract
Paclitaxel is a most widely used anticancer drug with low oral bioavailability, thus it is currently administered via intravenous infusion. DHP107 is a lipid-based paclitaxel formulation that can be administered as an oral solution. In this study, we investigated the mechanism of paclitaxel absorption after oral administration of DHP107 in mice and rats by changing the dosing interval, and evaluated the influence of bile excretion. DHP107 was orally administered to mice at various dosing intervals (2, 4, 8, 12, 24 h) to examine how residual DHP107 affected paclitaxel absorption during subsequent administration. Studies with small-angle X-ray diffraction (SAXS) and cryo-transmission electron microscopy (cryo-TEM) showed that DHP107 formed a lipidic sponge phase after hydration. The AUC values after the second dose were smaller than those after the first dose, which was correlated to the induction of expression of P-gp and CYP in the livers and small intestines from 2 h to 7 d after the first dose. The smaller AUC value observed after the second dose was also attributed to the intestinal adhesion of residual formulation. The adhered DHP107 may have been removed by ingested food, thus resulting in a higher AUC. In ex vivo and in vivo mucoadhesion studies, the formulation adhered to the villi for up to 24 h, and the amount of DHP107 that adhered was approximately half that of monoolein. The paclitaxel absorption after administration of DHP107 was not affected by bile in the cholecystectomy mice. The dosing interval and food intake affect the oral absorption of paclitaxel from DHP107, which forms a mucoadhesive sponge phase after hydration. Bile excretion does not affect the absorption of paclitaxel from DHP107 in vivo.
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Acknowledgements
This study was supported by an intramural grant from the Korea Institute of Science and Technology (No 2E24670) and a grant from the Korea Evaluation Institute of Industrial Technology (No 10044731).
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Supplementary information is available on Acta Pharmacologica Sinica's web site.
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Supplementary Figure S1
Diffraction patterns of F109 and DHP107 at various hydrations at room temperature. (DOC 448 kb)
Supplementary Figure S2
AUC of paclitaxel in plasma after oral administration of (A) single DHP107 and (B) second dose of DHP107 administered 2, 4, 8, 24, 48, and 96 h after administration of DHP107 (solid bars) and F109 (empty bars) under fasted and fed conditions. The doses of DHP107 and F109 were 50 mg/kg and 5 mL/kg, respectively. (DOC 253 kb)
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Jang, Y., Chung, H., Hong, J. et al. Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase. Acta Pharmacol Sin 38, 133–145 (2017). https://doi.org/10.1038/aps.2016.105
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DOI: https://doi.org/10.1038/aps.2016.105
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