Индивидуальная восприимчивость больных туберкулезом к изониазиду зависит от вариабельности его фармакокинетики, обусловленной полиморфизмом гена N-ацетилтрансферазы 2. Фармакокинетические параметры изониазида – максимальная и минимальная равновесные концентрации, время достижения максимальной концентрации, время, в течение которого концентрация превышает среднюю концентрацию в плазме, константа элиминации, период полуэлиминации не отличаются у пациентов с медленным, промежуточным и быстрым типом ацетилирования (p > 0,05). У пациентов с быстрым типом ацетилирования площадь под фармакокинетической кривой и средняя концентрация изониазида в плазме ниже, чем у пациентов с медленным типом ацетилирования (p = 0,0076 и p = 0,0073 соответственно). У пациентов с медленным типом ацетилирования слабее выражен разброс концентраций изониазида в плазме, чем у обладающих промежуточным и быстрым типом ацетилирования (p = 0,0002 и p = 0,0124 соответственно). Фармакокинетические показатели изониазида были одинаковыми у лиц с промежуточным и быстрым уровнем ацетилиорования.

Background. Individual sensitivity to isoniazid in tuberculosis patients is determined by the presence of N-acetyltransferase 2 (NAT2) enzyme gene allelic variants in genome. Evaluation of quantitative and qualitative alterations in peripheral blood can be used for diagnosis, disease severity estimation, or as a clue for estimation of anti-tuberculosis chemotherapy effectiveness and safety. Aim: Find associations between acetylation type and peripheral red blood cell (RBC) dynamics; determine the effect of NAT2 acetylation rate on the effectiveness and safety of treatment in patients with newly identified pulmonary tuberculosis (TB) residing in the Sakha Republic (Yakutia). Methods. This study included 146 patients with various clinical forms of newly diagnosed pulmonary TB. Oral isoniazid, rifampicin, pyrazinamide, and ethambutol were administered patients. Genotyping was performed via real time PCR. Results. Rapid and intermediate acetylators showed an increase in hemoglobin concentrations and RBC erythrocyte hemoglobin content by the end of chemotherapy (P<0.05). Incidence of anemia was lower in intermediate acetylators, compared to rapid or slow acetylators (P=0.013). Negative correlation was established between absolute RBC count and slow acetylation type (P=0.017). Patients with rapid acetylation type showed increased RBC distribution width indexes RDW-CV and RDW-SD (P<0.05). Conclusions. An adequate therapeutic effect was achieved with standard doses of anti-TB medications in patients with intermediate acetylation type. Rapid and slow acetylators required anti-TB medication dose correction. Genotyping for NAT2 gene in patients with pulmonary TB enables clinicians to choose the optimal dose of anti-TB medications, specifically, isoniazid dose.

To assess the risk of insufficient response or adverse reactions to standard doses of anti-TB drugs, it was proposed to use pharmacogenetic testing of genes of enzymes that metabolize these drugs. Since the frequency of genotypes varies depending on patients’ ethnicity, it is necessary to conduct studies among ethnic groups. The aim of this study was to identify the types of N-acetyltransferase 2 (NAT2) polymorphisms and phenotypes and their prevalence among Yakutian tuberculosis patients, as well as to conduct a comparative analysis with Russian patients. In total 158 patients were examined using real-time PCR: 50 – Yakutians, 41 – Russians (Yakutia), 67 – Russians (Moscow region). Six NAT2 polymorphisms were identified (*5, *6, *7, *11, *12, *13). Significant differences in the distribution of NAT2*5, *11, *12 between Yakutians and Russians were found: these polymorphisms prevail among Russian patients. The frequency of rapid phenotype among Yakutians is higher compared to Russians. The data obtained can contribute to the improvement of the antituberculosis therapy effectiveness in Yakutian patients.

Background. Tuberculosis therapy can lead to considerably dissimilar outcomes among individual patients. Some patients benefit from anti-tuberculosis chemotherapy leading to a desired therapeutic effect, while other patients show insufficient or absent response, or develop adverse side effects. Individual response to isoniazid is affected by mutations in the gene encoding N-acetyltransferase 2 (NAT2). Wide variations were observed in distributions of polymorphic NAT2 alleles in human populations depending on race, ethnicity, or geographical origin. No data are available to date on prevalence of NAT2 gene polymorphic variants and acetylation types in Yakut (Sakha) patients with newly diagnosed pulmonary tuberculosis. Aims: the frequencies of NAT2 polymorphic SNPs as well isoniazid acetylation phenotypes were evaluated in the patients cohort of Yakut ethnicity with newly diagnosed pulmonary tuberculosis (PTB). The comparison with, other ethnic groups of Asian origin was done. Methods. Cross-sectional study was conducted among Yakut patient cohorts with newly identified pulmonary tuberculosis. Using real-time PCR the following SNPs were explored: NAT2*5 (rs1801280, Т341С), NAT2*6 (rs1799930, G590A), NAT2*7 (rs1799931, G857A), NAT2*11 (rs1799929, C481T), NAT2*12 (rs1208, A803G), NAT2*13 (rs1041983, C282T). Genetically determined metabolic rates were calculated using NATpred online tool. Results. NAT2 SNPs were assessed, namely *5, *6, *7, *11, *12, and *13. The most frequent in Yakut patients were NAT2*6 and NAT2*13 SNPs (40.9% and 64.4%, respectively). Significant differences were detected in frequencies of NAT2 *5, *11, *12 polymorphisms; all studied NAT2 gene polymorphisms showed meaningful differences in genotype and minor allele prevalence rates after comparison between Yakut population and other Mongoloid ethnic groups (populations of China, Japan, Vietnam). High prevalence of intermediate acetylation type among ethnic Yakuts (58.3%) was established. Conclusions. Certain distinct differences in allelic variants of NAT2 gene and acetylation type prevalence in patients of Yakut ethnic origin newly diagnosed with pulmonary tuberculosis let conclude that the existing genotyping and phenotyping data from studies among other Mongoloid populations cannot be implicitly extrapolated on Yakut people. Pharmacogenetic data on individual response to drugs in Yakut patients should be made use of in clinical practice, to develop personalized isoniazid administration algorithms, with a final goal to make treatment more effective and safe.

The investigation of 49 clinical strains of M. tuberculosis (MBT) was performed for determination of genetic markers of resistance of first and second lines of anti-TB drugs. For each of isolates the individual profile from six genetic markers of resistance to rifampicin, isoniazid, ethambutol, aminoglycosides and fluoroquinolones has been obtained. DNA sequence of katG, rpoB, embB, rrs and two promoter regions of inhA and eis genes were determined for MBT from patients with primary TB living in Irkutsk Oblast and Republic of Sakha (Yakutia).