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.

Automated summary

Glucocorticoids reduced C-min/dose levels of VRC and different SNPs of CYP450 have varied effects on the C-min/dose ratio of VRC. Glucocorticoids and CYP2C19*17 mutants had a synergistic effect in reducing VRC C-min/dose. The clinical efficacy of VRC should be carefully monitored, especially in the presence of CYP2C19*17 mutants when combined with glucocorticoids.