title: Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase.
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.
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.|School of Life Sciences and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Yura
authors.initials: Y
authors.lastname: Jang
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam 52828, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Jung Wan
authors.initials: JW
authors.lastname: Hong
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Cheol-Won
authors.initials: CW
authors.lastname: Yun
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Hesson
authors.initials: H
authors.lastname: Chung
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D002210:Caprylates / Q000737:chemistry; D065727:Cytochrome P-450 CYP2C8 / Q000096:biosynthesis; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D004334:Drug Administration Schedule; D004339:Drug Compounding; D004435:Eating; D005260:Female; D005989:Glycerides / Q000737:chemistry / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism; D008055:Lipids / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009821:Oils / Q000737:chemistry / Q000493:pharmacokinetics*; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011136:Polysorbates / Q000737:chemistry; D051381:Rats; D014280:Triglycerides / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002210:Caprylates; D005989:Glycerides; D008055:Lipids; D009821:Oils; D011136:Polysorbates; D014280:Triglycerides; C003637:tricaprylin; C005953:monoolein; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel