Mapping the potential of pharmaco-metabolomics for personalized antituberculosis therapy

The concept of personalized medicine aims to improve therapeutic response and to minimize adverse drug reactions. Polymorphic enzymes involved in drug metabolism may influence the systemic concentration of the drug. The aim of this study was to explore possible associations between the kinetics of isoniazid (INH) metabolism and genetic polymorphisms of isoniazid-metabolizing enzymes in Latvian tuberculosis patients. Samples were obtained from patients at 2 h after the intake of antituberculosis drugs. Plasma levels of INH, acetylisoniazid (AcINH) and isonicotinic acid (INA) were detected using Liquid Chromatography-Tandem Mass Spectrometry. Genotyping of N-acetyltransferase 2 (NAT2) gene was performed by 7-SNP panel identification. NAT2 phenotype (slow acetylator, SA; intermediate acetylator, IA) was assigned based on the obtained genotyping data. Glutation-S-transferase M1 class (GSTM1) class null/plus genotype assay was carried out by a comparative duplex PCR. The impact of the genotype on the metabolic INH ratios was determined using multivariate ANOVA. All statistical analyses were performed using XLSTAT analysis package. Data comprises 33 patients (23 males and 10 females); age range 19 - 82 years. The NAT2/GSTM1 genotype significantly influenced the metabolic ratio of AcINH/INH (P=0.0001, R2 = 0.637); mean AcINH/INH ratios were 1.206 (SD 0.714), 1.191 (SD 0.390), 0.266 (SD 0.135), and 0.322 (SD 0.250) for NAT2_IA/GSTM1_null, NAT2_IA/GSTM1_plus, NAT2_SA/GSTM1_null, and NAT2_SA/GSTM1-plus genotype, respectively. Also, NAT2/GSTM1 genotype significantly influenced the INA/INH metabolic ratio (P=0.002, R2 = 0.395): mean INA/INH ratios were 0.250 (SD 0.157), 0.223 (SD 0.092), 0.079 (SD 0.061) and 0.109 (SD 0.081) for NAT2_IA/GSTM1_null, NAT2_IA/GSTM1_plus, NAT2_SA/GSTM1_null and NAT2_SA/GSTM1_plus genotypes, respectively. In order to increase the capacity of therapeutic drug monitoring and to assess the merits of genotyping and dose adjustment in isoniazid treatment more research is needed in a larger cohort. Acknowledgements. This study was supported by the Latvian Council of Science project No lzp-2020/1-0050.