Voriconazole is the first-line drug for invasive aspergillosis infection treatment. It is metabolized via cytochrome P450 2C19 (CYP2C19), cytochrome P450 3A4 (CYP3A4) and flavin-containing monooxygenase 3 (FMO3). Many studies revealed the correlation between genetic polymorphisms of these SNPs and voriconazole metabolism. Several mutations, however, have not been reported in Thai population. Therefore, this study investigated the prevalence of CYP2C19, CYP3A4 and FMO3 polymorphisms. Two hundred and forty-nine healthy northeastern Thai volunteers who were blood donors at Srinagarind Hospital blood bank were enrolled. CYP2C19 (*2, *3, *17), CYP3A4 (*22, rs4646437G>A) and FMO3 (rs2266782G>A, rs2266780A>G) mutations were investigated. The allele frequencies were CYP2C19*1 (0.72), *2 (0.24), *3 (0.03) and *17 (0.02) in this study. They were significantly different from Caucasian and Japanese populations. Moreover, CYP3A4 rs4646437 allele frequencies were 0.76 for "G" and 0.24 for "A" alleles. The mutation of CYP3A4*22 was not found in this study. Wild type (G) and mutation (A) allele frequencies of FMO3 rs2266782 were 0.86 and 0.14, respectively. Similarly, the allele frequencies of FMO3 rs2266780 for "A" (wild type) and "G" (mutant) were 0.89 and 0.11, respectively. Furthermore, a strong linkage disequilibrium was found between FMO3 rs2266782 and rs2266780 genes (D = 0.955, r 2 = 0.7021). The information on the SNP frequencies of CYP2C19, CYP3A4 and FMO3 in Thais was found to be significantly different from other populations. The genotype prevalence may be the preliminary information for a further clinical study to investigate the association between these genotypes and voriconazole treatment outcomes.

Background: Voriconazole (VCZ) is prescribed worldwide for invasive fungal infection. VCZ is predominantly metabolized by CYP2C19 and CYP3A4 enzymes. Recent reports revealed CYP3A4 has become an important enzyme for the VCZ metabolism in patients with poor activity of CYP2C19. CYP3A4 mutant alleles such as rs4646437 and CYP3A4*22 influence VCZ concentration. CYP3A4*22 was found in Caucasians but null in East Asian population. CYP3A4 rs4646437 was found in Asian and Caucasian populations. The prevalence of CYP3A4*22 and CYP3A4 rs4646437 were not investigated in Thais. The correlation between CYP3A4 rs4646437 polymorphisms and VCZ dosage regimen was limited. Therefore, the aim of this study was to determine the correlation between CYP3A4 rs4646437 polymorphisms and VCZ dosage regimen in Thai patients with invasive fungal infection. Moreover, we investigated prevalence of CYP3A4 rs4646437 and CYP3A4*22 in Thai healthy volunteers.Material and Method: One hundred healthy volunteers were enrolled from blood donors at blood blank of Srinagarind Hospital. Forty five invasive fungal infected patients treated with VCZ at Srinagarind and Ramathibodi hospital were enrolled. VCZ blood concentrations were determined at steady state (≥5 th day after treatment) and all of the blood levels were in therapeutic range. Clinical data of the patients were reviewed. CYP3A4 polymorphisms was determined by realtime PCR technique with specific TaqMan® probe and primer. VCZ blood concentration was determined by HPLC method.Result: Genotype frequencies for CYP3A4 rs4646437 GG, GA and AA in 100 Thai healthy volunteers were 65%, 28%, and 7%, respectively. CYP3A4*22 mutant allele was not found in Thais. The genotype frequencies of CYP3A4 rs4646437 showed a statistically significant difference from Chinese and Caucasian populations (P<0.005). The frequencies of CYP3A4 rs4646437 GG, GA, and AA in 47 pateints were 68.9%, 26.7%, and 4.4%, respectively. VCZ dosages at steady state for the patients carrying CYP3A4 rs4646437 GG, GA and AA did not show a statistically significant difference (7.79 ±1.93 VS 6.97±1.58 VS 9.80±1.92 mg/kg/day, respectively) (P= 0.118).Conclusion: Homozygous mutant of CYP3A4 rs4646437 in healthy Thai volunteers was higher than other populations. Correlation between CYP3A4 rs4646437 mutant alleles and VCZ doses was not found in this study.