Impact ofCYP2C19,CYP3A4,ABCB1, andFMO3genotypes on plasma voriconazole in Thai patients with invasive fungal infections

Abstract

Voriconazole is the first‐line antifungal choice in the treatment of invasive fungal infections (IFIs). Single nucleotide polymorphisms (SNPs) in drug‐metabolizing and transporter genes may affect voriconazole pharmacokinetics. This study aimed to determine the frequency of the CYP2C19 rs4244285, rs4986893, rs72552267, and rs12248560, CYP3A4 rs4646437, ABCB1 rs1045642, and FMO3 rs2266782 alleles and determine the association between these genetic variants and voriconazole concentrations in Thai patients with invasive fungal infections. The study comprised 177 Thai patients with IFIs in whom seven SNPs in CYP2C19 , CYP3A4 , ABCB1, and FMO3 were genotyped using Taq Man real‐time polymerase chain reaction (RT‐PCR) 5´ nuclease assays, and voriconazole plasma concentrations were measured by high‐performance liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Of the 177 patients included, 31 were <12 years and 146 were ≥12 years. The CYP2C19 allele frequencies were 0.29 for *2 , 0.060 for *3 , 0.003 for *6 , and 0.008 for *17 . The allele frequency of CYP3A4 (rs4646437) was 0.26, ABCB1 (rs1045642) was 0.36, and FMO3 (rs2266782) was 0.16. The median voriconazole dose/weight was significantly lower in patients aged ≥12 years when compared to the patients aged <12 years ( P < .001). Patients aged <12 years with CYP2C19*1/*2 exhibited significantly higher median voriconazole plasma concentrations than those with the CYP2C19*1/*1 ( P = .038). However, there were no significant differences in median voriconazole plasma concentrations among the CYP2C19 genotypes in the patients aged ≥12 years. There was a lack of association observed among the CYP3A4, ABCB1, and FMO3 genotypes on the plasma voriconazole concentrations in both groups of patients. Our findings indicate that voriconazole plasma concentrations are affected by the CYP2C19*2 allele in patients aged <12 years but not in patients aged ≥12 years.

Effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole levels in Chinese pediatric patients

“…In this study, the allele frequency of CYP3A4 rs4646437 was 30.9%, but no significant difference in voriconazole plasma levels between the noncarriers and carriers. Our results corroborate a report by Chuwongwattana et al [33]. In agreement with a previous study involving 86 Chinese subjects [34], the CYP3A4*22 allele carriers were not observed in this research.…”

“…Our results corroborate a report by Chuwongwattana et al . [33]. In agreement with a previous study involving 86 Chinese subjects [34], the CYP3A4*22 allele carriers were not observed in this research.…”

Rapid Pyrosequencing Method for FMO3 Non-Synonymous Genetic Variant Evaluation in A Korean Population

“…Various methods have been suggested for the analysis of the targeted SNPs. For example, FMO3-related SNPs were detected by PCR-restriction fragment length polymorphism [24], real-time PCR [25], or direct sequencing methods [26]. The automated sequencing method was rst introduced in the 1970s by Frederick Sanger [27].…”

Rapid detection ofFMO3single nucleotide polymorphisms using a pyrosequencing method

“…Various methods have been proposed to analyze the targeted SNPs. For example, FMO3 -related SNPs have been detected by using PCR-restriction fragment length polymorphism analysis ( 19 ), real-time PCR ( 20 ) and direct sequencing methods ( 21 ). Sequencing technology was first conceptualized and developed in the 1970s by Sanger et al ( 22 ).…”

“…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 ).…”