Biopharmaceutical Properties of Tubeimoside-1: A Cytotoxic Amphipathic Cyclic Bisdesmoside

Keisuke Oda,Nobuhiro Mori,Tomomi Umakoshi,Ryoji Kasai,Teruo Murakami

doi:10.15344/2456-3501/2017/126

Keisuke Oda, Nobuhiro Mori + Show 3 more

Open Access

https://doi.org/10.15344/2456-3501/2017/126

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Abstract

Background: Biopharmaceutical properties of tubeimoside-1, a cytotoxic amphipathic cyclic bisdesmoside, were evaluated to search for the usefulness of tubeimoside-1. Methods: Using tubeimoside-1, the solubilizing activity to itraconazole, effect on oral absorption of itraconazole in rats, stability in aqueous solution and intestinal homogenate, cytotoxicity to Caco- 2 cells, and membrane permeability across rat intestine and Caco-2 cell monolayers were evaluated. Concentrations of tubeimoside-1 were analyzed by LC-MS. Results: The solubility of itraconazole was 38.0 μg/mL in water containing 2.5% propylene glycol. Tubeimoside-1 and hydroxypropyl-β-cyclodextrin at a concentration of 10% increased itraconazole solubility to 6.5 mg/mL and 0.72 mg/mL, respectively. In rats, coadministration of tubeimoside-1 (10%) significantly increased the oral absorption of itraconazole, however, the enhancing effect was almost half of hydroxypropyl-β-cyclodextrin (10%). Tubeimoside-1 was gradually degraded under acidic condition and in S9 fraction of intestinal mucosal homogenates. The cytotoxicity of tubeimoside-1 was observed in Caco-2 cells. The membrane permeability of tubeimoside-1 was almost negligible in rat intestine in situ and Caco-2 cell monolayers in vitro. Conclusions: Greater solubilizing activity and biodegradability of tubeimoside-1, in addition to cytotoxicity, were observed. Further study is necessary to search for the usefulness of tubeimoside-1 as a strong solubilizer by forming inclusion complex with lipophilic compounds.

Highlights

Steamed and dried tubers of Bolbostemma paniculatum (MAXIM.) FRANQUET (Cucurbitaceae), named as "Tu Bei Mu", has been used as an anti-inflammatory agent for mastitis and an antidote for snake skin in China, and tubeimoside-1 (T-1), a cyclic bisdesmoside, was isolated as one of active ingredients from the methanolic extract of the tubers (Figure 1) [1,2]
Tubeimoside-1 was gradually degraded under acidic condition and in S9 fraction of intestinal mucosal homogenates
The cytotoxicity of tubeimoside-1 was observed in Caco-2 cells

Summary

Introduction

Steamed and dried tubers of Bolbostemma paniculatum (MAXIM.) FRANQUET (Cucurbitaceae), named as "Tu Bei Mu", has been used as an anti-inflammatory agent for mastitis and an antidote for snake skin in China, and tubeimoside-1 (T-1), a cyclic bisdesmoside, was isolated as one of active ingredients from the methanolic extract of the tubers (Figure 1) [1,2]. T-1, an amphiphilic compound having a relatively lipophilic exterior surface and nonpolar interior cavity, increased the solubility of poorly water soluble compounds such as Saponin A, Yellow OB and α-tocopherol [1,5]. In the present study, using T-1, the solubilizing activity to itraconazole (ITZ), effect on oral absorption of ITZ in rats, stability in aqueous buffer and intestinal homogenate, cytotoxicity to Caco-2 cells, and membrane permeability across rat small intestine and Caco-2 cell monolayers were examined to understand the biopharmaceutical properties of unique amphipathic inclusion compound and to search for the usefulness of T-1. Itraconazole (ITZ) and hydroxypropyl-βcyclodextrine (HPβCD) were used as a poor water-soluble compound and a potent inclusion compound, respectively [6]. As clinically available formulation of ITZ, ITZ (10 mg/mL) is solubilized by 40% HPβCD to form a molecular inclusion complex (SPORANOX® (itraconazole) Oral Solution, Janssen Pharmaceutica N.V. Beerse, Belgium)

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