Interactive Effects of Glucocorticoids and Cytochrome P450 Polymorphisms on the Plasma Trough Concentrations of Voriconazole

Abstract

<b>Aims:</b> To explore the interactive influence of glucocorticoids and cytochrome P450 (CYP450) polymorphisms on voriconazole (VRC) plasma trough concentrations (C_min) and provide a reliable basis for reasonable application of VRC. <b>Methods:</b> A total of 918 VRC C_min from 231 patients was collected and quantified using high-performance liquid chromatography in this study. The genotypes of <i>CYP2C19</i>, <i>CYP3A4</i>, and <i>CYP3A5</i> were detected by DNA sequencing assay. The effects of different genotypes and the coadministration of glucocorticoids on VRC C_min were investigated. Furthermore, the interactive effects of glucocorticoids with CYP450s on VRC C_min were also analyzed. <b>Results:</b> The median C_min of oral administration was lower than that of intravenous administration (1.51 vs. 4.0 mg l^-1). Coadministration of glucocorticoids (including dexamethasone, prednisone, prednisolone, and methylprednisolone) reduced the VRC C_min/dose, respectively, among which dexamethasone make the median of the VRC C_min/dose ratio lower. As a result, when VRC was coadministrated with glucocorticoids, the proportion of VRC C_min/dose in the subtherapeutic window was increased. Different CYP450 genotypes have different effects on the C_min/dose of VRC. Mutations of <i>CYP2C19*2</i> and <i>*3</i> increased C_min/dose of VRC, while <i>CYP2C19*17</i> and <i>CYP3A4</i> rs4646437 polymorphisms decreased C_min/dose of VRC. The mutation of <i>CYP3A5</i> has no significant effect. Furthermore, <i>CYP2C19*17</i> mutants could strengthen the effects of glucocorticoids and decrease VRC C_min/dose to a larger extent. <b>Conclusion:</b> Our study revealed that glucocorticoids reduced the C_min/dose levels of VRC and different SNPs of CYP450 have different effects on the C_min/dose ratio of VRC. Glucocorticoids and <i>CYP2C19*17</i> mutants had a synergistic effect on reducing VRC C_min/dose. The present results suggested that when VRC is combined with glucocorticoids, we should pay more attention to the clinical efficacy of VRC, especially when <i>CYP2C19*17</i> mutants exist.