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

Aims: 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. Methods: 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 CYP2C19 , CYP3A4 , and CYP3A5 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. Results: 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 CYP2C19*2 and *3 increased C min /dose of VRC, while CYP2C19*17 and CYP3A4 rs4646437 polymorphisms decreased C min /dose of VRC. The mutation of CYP3A5 has no significant effect. Furthermore, CYP2C19*17 mutants could strengthen the effects of glucocorticoids and decrease VRC C min /dose to a larger extent. Conclusion: 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 CYP2C19*17 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 CYP2C19*17 mutants exist.