Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

Yura Jang, Hye Jin Chung, Jung Wan Hong, Cheol-Won Yun, Hesson Chung

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)133-145
Number of pages13
JournalActa Pharmacologica Sinica
Volume38
Issue number1
DOIs
Publication statusPublished - 2017 Jan 1

Fingerprint

Porifera
Paclitaxel
Bile
Area Under Curve
Cryoelectron Microscopy
Cholecystectomy
Transmission Electron Microscopy
Intravenous Infusions
X-Ray Diffraction
Biological Availability
Small Intestine
Oral Administration
Eating
Lipids
Food
Liver
Pharmaceutical Preparations

Keywords

  • CYP
  • DHP107
  • dosing regimen
  • drug absorption
  • mucoadhesiveness
  • oral formulation
  • P-gp
  • paclitaxel
  • sponge phase

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase. / Jang, Yura; Chung, Hye Jin; Hong, Jung Wan; Yun, Cheol-Won; Chung, Hesson.

In: Acta Pharmacologica Sinica, Vol. 38, No. 1, 01.01.2017, p. 133-145.

Research output: Contribution to journalArticle

Jang, Yura ; Chung, Hye Jin ; Hong, Jung Wan ; Yun, Cheol-Won ; Chung, Hesson. / Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase. In: Acta Pharmacologica Sinica. 2017 ; Vol. 38, No. 1. pp. 133-145.
@article{fae761c4bd854eb59c2127e03eaddb14,
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.",
keywords = "CYP, DHP107, dosing regimen, drug absorption, mucoadhesiveness, oral formulation, P-gp, paclitaxel, sponge phase",
author = "Yura Jang and Chung, {Hye Jin} and Hong, {Jung Wan} and Cheol-Won Yun and Hesson Chung",
year = "2017",
month = "1",
day = "1",
doi = "10.1038/aps.2016.105",
language = "English",
volume = "38",
pages = "133--145",
journal = "Acta Pharmacologica Sinica",
issn = "1671-4083",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

AU - Jang, Yura

AU - Chung, Hye Jin

AU - Hong, Jung Wan

AU - Yun, Cheol-Won

AU - Chung, Hesson

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - CYP

KW - DHP107

KW - dosing regimen

KW - drug absorption

KW - mucoadhesiveness

KW - oral formulation

KW - P-gp

KW - paclitaxel

KW - sponge phase

UR - http://www.scopus.com/inward/record.url?scp=85008613502&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85008613502&partnerID=8YFLogxK

U2 - 10.1038/aps.2016.105

DO - 10.1038/aps.2016.105

M3 - Article

C2 - 27867185

AN - SCOPUS:85008613502

VL - 38

SP - 133

EP - 145

JO - Acta Pharmacologica Sinica

JF - Acta Pharmacologica Sinica

SN - 1671-4083

IS - 1

ER -