Predictive Value of FMO3 Variants on Plasma Disposition and Adverse Reactions of Oral Voriconazole in Febrile Neutropenia

Abstract

Background and Objectives: With the increasing number of patients with febrile neutropenia (FN), voriconazole (VRC) has been widely used in hospitals for first-line treatment of FN. The study was designed for evaluating the influence of FMO3 mutation on the plasma disposition and adverse reactions of VRC in FN. Materials and Methods: A single-center observational study was conducted in the inpatient ward for 4 years. The genotypes of FMO3 and cytochrome P450 (CYP) 2C19 were detected by PCR-restriction fragment length polymorphism. Patients with neutropenia were screened according to the CYP2C19 metabolic phenotype and other inclusion criteria. Five days after empirical administration of VRC, blood concentrations of VRC and nitrogen oxides in patients' blood were determined by liquid chromatographyelectrospray tandem mass spectrometry (LC-ESI MS/MS). Serum parameters and clinical adverse reaction symptoms in the medical records were collected and statistically analyzed. Results: A total of 165 patients with neutropenia with the intermediate metabolic phenotype of CYP2C19 were screened. At the initial stage of oral VRC treatment, patients with the FMO3 E308G genotype had a poorer plasma disposal ability to VRC than those with the wide type of FMO3 (WT) genotype (p = 0.0005). Moreover, patients with the FMO3 E308G genotype were more likely to have adverse drug reactions and abnormal serum parameters after receiving VRC treatment. For example, the serum potassium level in the FMO3 E308G genotype group was significantly lower than that in the WT group (p = 0.028), the abnormal level of total bilirubin in the FMO3 E308G genotype group was significantly higher than that in the WT group (p = 0.049), and the aspartate aminotransferase level in the E308G group was significantly higher than that in the WT group (p = 0.05). The incidence of atopic dermatitis and visual impairment in the FMO3 E308G genotype group was 67 and 75%, respectively, and the incidences of peripheral neuroedema, headache, and diarrhea were 57, 50, and 60%, respectively, which were significantly different from those in the WT group. Conclusion: FMO3 E308G reduces the activity of the FMO3 enzyme by decreasing the metabolic ability of VRC, which increases the plasma concentration of VRC and may also lead to adverse reactions in patients with FN.

Bacteroides Fragilis Polysaccharide A Ameliorates Abnormal Voriconazole Metabolism Accompanied With the Inhibition of TLR4/NF-κB Pathway

“…Clinical information was collected and ADRs were recorded in an earlier study ( Wang et al, 2020 ). A 5 ml sodium -heparin tube was used for blood sample collection.…”

“…Lipid LC-MS/MS was conducted as previously described ( Wang et al, 2020 ). A Waters UPLC-TOF-MS (Waters ACQUITY UPLC™ System Tandem Waters LCT Premier XE TOF-MS; Waters Corp., Milford, MA, United States) was usedto determine plasma VRC and VRC N-oxide.…”

“…Lipid LC-MS/MS was conducted as previously described (Wang et al, 2020 To investigate the roles of gut microbiota in adverse reaction development and modulation in patients, we analysed metagenomic sequence data extracted from the NCBI Sequencing Read Archive database using faecal samples from individuals with and without adverse reactions. DNA extraction and quality control were performed as previously described (Taur et al, 2012).…”

Rapid detection ofFMO3single nucleotide polymorphisms using a pyrosequencing method

“…Studies by Park et al (13) and Sung et al (14) demonstrated that the SnPs c.855c>T and c.472G>a affected the pharmacokinetics of sulindac in women who underwent preterm labor. Febrile neutropenia, myelosuppression and agranulocytosis related to these SnPs have also been reported previously (25,29,30). considering the relatively high frequency of FMO3 genetic polymorphisms in the population, the functional defects in FMo3 enzymes associated with these SnPs may have notable clinical implications, such as the variations in drug exposure followed by toxicity or delayed elimination of toxic substances.…”

“…FMO3 genetic polymorphisms have been the focus of considerable interest in research; these findings can be applied to various studies on the pharmacokinetics of various medications, including anti-diabetics (e.g., teneligliptin) ( 5 , 6 ), antibiotics (e.g., voriconazole) ( 20 , 25 ) and non-steroidal anti-inflammatory drugs (e.g., sulindac) ( 4 , 13 , 14 ), as well as human diseases, such as cardiovascular disorders ( 2 , 7 ). FMO3 increases plasma trimethylamine N-oxide (TMAO) levels by catalyzing the conversion of trimethylamine (TMA) derived from the gut microbiome ( 26 , 27 ).…”