title: Extracts of Immature Orange(Aurantii fructus immaturus)and Citrus Unshiu Peel(Citri unshiu pericarpium)Induce P-Glycoprotein and Cytochrome P450 3A4 Expression via Upregulation of Pregnane X Receptor.
abstract: P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) are expressed in the intestine and are associated with drug absorption and metabolism. Pregnane X receptor (PXR) is the key molecule that regulates the expression of P-gp and CYP3A4. Given that PXR activity is regulated by a variety of compounds, it is possible that unknown PXR activators exist among known medicines. Kampo is a Japanese traditional medicine composed of various natural compounds. In particular, immature orange [Aurantii fructus immaturus(IO)] and citrus unshiu peel [Citri unshiu pericarpium(CP)] are common ingredients of kampo. A previous study reported that kampo containing IO or CP decreased the blood concentration of concomitant drugs via upregulation of CYP3A4 although the mechanism was unclear. Some flavonoids are indicated to alter P-gp and CYP3A4 activity via changes in PXR activity. Because IO and CP include various flavonoids, we speculated that the activity of P-gp and CYP3A4 in the intestine may be altered via changes in PXR activity when IO or CP is administered. We tested this hypothesis by using LS180 intestinal epithelial cells. The ethanol extract of IO contained narirutin and naringin, and that of CP contained narirutin and hesperidin. Ethanol extracts of IO and CP induced P-gp, CYP3A4, and PXR expression. The increase of P-gp and CYP3A4 expression by the IO and CP ethanol extracts was inhibited by ketoconazole, an inhibitor of PXR activation. The ethanol extract of IO and CP decreased the intracellular concentration of digoxin, a P-gp substrate, and this decrease was inhibited by cyclosporine A, a P-gp inhibitor. In contrast, CP, but not IO, stimulated the metabolism of testosterone, a CYP3A4 substrate, and this was inhibited by a CYP3A4 inhibitor. These findings indicate that the ethanol extract of IO and CP increased P-gp and CYP3A4 expression via induction of PXR protein. Moreover, this induction decreased the intracellular substrate concentration.
authors.affiliation: Department of Clinical Pharmacy Practice Pedagogy, Institute of Biomedical Sciences, Tokushima University Graduate SchoolTokushima, Japan; Department of Pharmacy, Tokushima University HospitalTokushima, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Okada
authors.affiliation: Department of Pharmacy, Tokushima University Hospital Tokushima, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Murakami
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima University Tokushima, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Urushizaki
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima University Tokushima, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Department of Clinical Pharmacy Practice Pedagogy, Institute of Biomedical Sciences, Tokushima University Graduate School Tokushima, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kawazoe
authors.affiliation: Department of Pharmacy, Tokushima University HospitalTokushima, Japan; Department of Clinical Pharmacy, Institute of Biomedical Sciences, Tokushima University Graduate SchoolTokushima, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishizawa
keywords: Drug–Drug Interaction; Kampo; P-glycoprotein; citrus unshiu peel; cytochrome P450 3A4; immature orange; pregnane X receptor