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To examine whether quercetin interacts with vitamin D receptor, we investigated the effects of quercetin on vitamin D receptor activity in human intestinal Caco-2 cells. The effects of quercetin on the expression of the vitamin D receptor target genes, vitamin D3 24-hydroxylase, cytochrome P450 3A4, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were measured using quantitative polymerase chain reaction. The vitamin D receptor siRNA was used to assess the involvement of the vitamin D receptor. Vitamin D receptor activation using a vitamin D responsive element-mediated cytochrome P450 3A4 reporter gene assay was investigated in Caco-2 cells transfected with human vitamin D receptor. We also studied the magnitude of the vitamin D receptor activation and/or synergism between 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] and quercetin-like flavonoids. Slight but significant increases in the mRNA expression of cytochrome P450 3A4, vitamin D3 24-hydroxylase, multidrug resistance protein 1, and transient receptor potential vanilloid type 6 were observed after 3 days of continual quercetin treatment. The silencing effect of vitamin D receptor by vitamin D receptor siRNA in Caco-2 cells significantly attenuated the induction of the vitamin D receptor target genes. Moreover, quercetin significantly enhanced cytochrome P450 3A4 reporter activity in Caco-2 cells in a dose-dependent manner, and the expression of exogenous vitamin D receptor further stimulated the vitamin D receptor activity. Quercetin-like flavonoids such as kaempferol stimulated the vitamin D receptor activity in a manner similar to that seen with quercetin. Taken together, the data indicates that quercetin upregulates cytochrome P450 3A4 and multidrug resistance protein 1 expression in Caco-2 cells likely via a vitamin D receptor-dependent pathway.

A rapid, simple, and accurate procedure was developed and validated for the simultaneous quantification of two anticancer agents, volitinib and gefitinib in rat plasma by high-performance liquid chromatography with tandem mass spectrometry. The samples were separated by gradient elution from a cyano column within five minutes, using 0.1% formic acid in acetonitrile and 10 mM ammonium formate solution (pH 3.0) as mobile phase. When plasma samples were deproteinated by adding methanol, the analytes in the extract were detected in the positive ionization mode with the tracer ion mass of 346.1 → 145.1 for volitinib and 446.8 → 128.1 for gefitinib. The assay was determined to be valid in the concentration ranges of 2 to 1000 ng/mL for volitinib, and of 1 to 500 ng/mL for gefitinib. Intra- and interday accuracies ranged from 88.0 to 104.7% for volitinib and from 90.3 to 101%, for gefitinib. The precision of the assay ranged from 2.1 to 9.71% for volitinib and 2.31 to 12.1% for gefitinib. This method was successfully applied to a pharmacokinetic study of volitinib and gefitinib after the administration of an intravenous or oral dose, indicating that the developed assay can be used to simultaneously determine the concentrations of volitinib and gefitinib in rat plasma.