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

ABSTRACT: 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.

SUBMITTER: Jia SJ

PROVIDER: S-EPMC8185288 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The effects of genetic variation of cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) on efavirenz (EFV) plasma concentration was evaluated among 312 HIV patients in Nairobi Kenya. The EFV plasma concentration at steady-state were determined using ultra-high-performance liquid chromatography with a tandem quadruple mass spectrometer (LC-MS/MS). Thirteen CYP2B6 (329G>T, 341T>C, 444 G>T/C, 15582C>T, 516G>T, 548T>G, 637T>C, 785A>G, 18492C>T, 835G>C, 1459C>T and 21563C>T) and one CAR (540C>T) single nucleotide polymorphisms (SNPs) were genotyped using real-time polymerase chain reaction. HIV drug resistance mutations were detected using an in-house genotypic assay. The EFV concentration of patients ranged from 4 ng/mL to 332697 ng/mL (median 2739.5 ng/mL, IQR 1878-4891.5 ng/mL). Overall, 22% patients had EFV concentrations beyond therapeutic range of 1000-4000 ng/mL (4.5%% < 1000 ng/mL and 31.7% > 4000 ng/mL). Five SNPs (15582C>T, 516G>T, 785A>G, 983T>C and 21563C>T) were associated with higher EFV plasma concentration while 18492C>T with lower EFV plasma concentration (p<0.05). Strong linkage disequilibrium (LD) was observed for 15582C>T, 516G>T, 785A>G, 18492C>T, 983T>C, 21563C>T, 1459C>T and CAR 540C>T. Sixteen haplotypes were observed and CTGCTTCC, CTGCTTCT, TTGCTTCT and CGACCCCT were associated with high EFV plasma concentration. In multivariate analysis, factors significantly associated with EFV plasma concentration included; the presence of skin rash (β = 1379, 95% confidence interval (CI) = 3216.9-3416.3; p < 0.039), T allele of CYP2B6 516G>T (β = 1868.9, 95% CI 3216.9-3416.3; p < 0.018), the C allele of CYP2B6 983T>C (β = 2638.3, 95% CI = 1348-3929; p < 0.0001), T allele of CYP2B6 21563C>T (β = 1737, 95% CI = 972.2-2681.9; p < 0.0001) and the presence of 5 to 7 numbers of SNPs per patient (β = 570, 95% CI = 362-778; p < 0.0001) and HIV viral load ≤1000 cells/mL (β = -4199.3, 95% CI = -7914.9 --483.6; p = 0.027). About 36.2% of the patients had EFV plasma concentrations beyond therapeutic window, posing high risk of treatment failure or toxicity. The SNPs of CYP2B6 516G>T, CYP2B6 983T>C, 21563C>T, presence of higher numbers of SNPs per patient and haplotypes CTGCTTCC, CTGCTTCT, TTGCTTCT and CGACCCCT could efficiently serves as genetic markers for EFV plasma concentration and could guide personalization of EFV based ART treatment in Kenya.

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

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