Impact of polymorphisms of pharmacokinetics-related genes and the inflammatory response on the metabolism of voriconazole

Abstract

The effects of inflammatory responses and polymorphisms of the genes encoding cytochrome P450 (CYP) (CYP2C19 and CYP3A5), flavin-containing monooxygenase 3 (FMO3), pregnane X receptor (NR1I2), constitutive androstane receptor (NR1I3), and CYP oxidoreductase (POR) on the ratio of voriconazole (VRCZ) N-oxide to VRCZ (VNO/VRCZ) and steady-state trough concentrations (C_0h ) of VRCZ were investigated. A total of 56 blood samples were collected from 36 Japanese patients. Results of multiple linear regression analyses demonstrated that the presence of the extensive metabolizer CYP2C19 genotype, the dose per administration, and the presence of the NR1I2 rs3814057 C/C genotype were independent factors influencing the VNO/VRCZ ratio in patients with CRP levels of less than 40 mg/L (standardized regression coefficients (SRC) = 0.448, -0.301, and 0.390, respectively; all p < .05). With regard to the concentration of VRCZ itself, in addition to the above factors, the presence of the NR1I2 rs7643645 G/G and rs3814055 T/T genotypes were found to be independent factors influencing the VRCZ C_0h in these patients (SRC = -0.430, 0.424, -0.326, 0.406 and -0.455, respectively; all p < .05). On the contrary, in patients with CRP levels of at least 40 mg/L, no independent factors were found to affect VNO/VRCZ and VRCZ C_0h . Inflammatory responses, and CYP2C19 and NR1I2 polymorphisms may be useful information for the individualization of VRCZ dosages.

Keywords: CRP; CYP2C19; NR1I2 polymorphism; voriconazole; voriconazole N-oxide.

FIGURE 1

Histograms of (A) VNO/VRCZ and (B) VRCZ C_0h. VRCZ, voriconazole; VNO/VRCZ, ratio of VRCZ N‐oxide of VRCZ; C_0h, steady‐state trough concentrations of VRCZ

FIGURE 2

Relationships of VNO/VRCZ to inflammation status. The concentrations of voriconazole (VRCZ), VRCZ N‐oxide (VNO), and C‐reactive protein (CRP) in patient blood plasma were determined as described in Materials and Methods

FIGURE 3

Comparison of VNO/VRCZ with respect to differences in inflammatory status and CYP2C19 genotype. The concentrations of voriconazole (VRCZ), VRCZ N‐oxide (VNO), and C‐reactive protein (CRP) in patient blood plasma were determined as described in Materials and Methods. Patient genotypes are as follows: EM (extensive metabolizer), CYP2C19 *1/*1; IM (intermediate metabolizer), CYP2C19 *1/*2 or *1/*3; PM (poor metabolizer), CYP2C19 *2/*2 or *2/*3 or *3/*3. Box and whisker plots were prepared with SPSS. The box spans data between two quartiles (IQR, interquartile range), with the median represented as a bold horizontal line. The ends of the whiskers (vertical lines) represent the smallest and largest values that were not outliers. Outliers (Ο) are values between 1.5 and 3 IQRs from the end of the box. The values above the upper limits of the y axis are shown with a scale break line. The values are expressed as median (IQR)

FIGURE 4

Comparison of C_0h/D with respect to the differences in inflammatory status and CYP2C19 genotype. VRCZ, voriconazole; VNO/VRCZ, ratio of VRCZ N‐oxide to VRCZ; C_0h, steady‐state trough concentrations of VRCZ; C_0h/D, VRCZ dose‐adjusted C_0h; CRP, C‐reactive protein. EM (extensive metabolizer), CYP2C19 *1/*1; IM (intermediate metabolizer), CYP2C19 *1/*2 or *1/*3; PM (poor metabolizer), CYP2C19 *2/*2 or *2/*3 or *3/*3. Graphical analysis was performed using an SPSS box and whiskers plot. The box spans data between two quartiles (IQR, interquartile range ), with the median represented as a bold horizontal line. The ends of the whiskers (vertical lines) represent the smallest and largest values that were not outliers. Outliers (Ο) are values between 1.5 and 3 IQRs from the end of the box. The values above the upper limits of the y axis are shown with a scale break line. The values are expressed as median (IQR)